TY  - JOUR
AU  - Hölter, S.
AU  - Cacheiro, P.*
AU  - Smedley, D.*
AU  - Kent Lloyd, K.C.*
C1  - 73095
C2  - 56896
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 384-389
TI  - IMPC impact on preclinical mouse models.
JO  - Mamm. Genome
VL  - 36
IS  - 2
PB  - Springer
PY  - 2025
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Hölter, S.M.
AU  - Garrett, L.
AU  - Bludau, S.*
AU  - Amunts, K.*
C1  - 71865
C2  - 56181
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 544-550
TI  - Digital tools of analysis and data integration facilitate synergy between mouse and human brain research and enable translation.
JO  - Mamm. Genome
VL  - 35
IS  - 4
PB  - Springer
PY  - 2024
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Over the last decade, INFRAFRONTIER has positioned itself as a world-class Research Infrastructure for the generation, phenotyping, archiving, and distribution of mouse models in Europe. The INFRAFRONTIER network consists of 22 partners from 15 countries, and is continuously enhancing and broadening its portfolio of resources and services that are offered to the research community on a non-profit basis. By bringing together European rodent model expertise and providing valuable disease model services to the biomedical research community, INFRAFRONTIER strives to push the accessibility of cutting-edge human disease modelling technologies across the European research landscape. This article highlights the latest INFRAFRONTIER developments and informs the research community about its extensively utilised services, resources, and technical developments, specifically the intricacies of the INFRAFRONTIER database, use of Curated Disease Models, overview of the INFRAFRONTIER Cancer and Rare Disease resources, and information about its main state-of-the-art services.
AU  - Ali Khan, A.
AU  - Valera Vazquez, G.*
AU  - Gustems, M.*
AU  - Matteoni, R.*
AU  - Song, F.*
AU  - Gormanns, P.*
AU  - Fessele, S.*
AU  - Raess, M.*
AU  - Hrabě de Angelis, M.
C1  - 68086
C2  - 54564
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 408-417
TI  - INFRAFRONTIER: Mouse model resources for modelling human diseases.
JO  - Mamm. Genome
VL  - 34
IS  - 3
PB  - Springer
PY  - 2023
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Echocardiography, a rapid and cost-effective imaging technique, assesses cardiac function and structure. Despite its popularity in cardiovascular medicine and clinical research, image-derived phenotypic measurements are manually performed, requiring expert knowledge and training. Notwithstanding great progress in deep-learning applications in small animal echocardiography, the focus has so far only been on images of anesthetized rodents. We present here a new algorithm specifically designed for echocardiograms acquired in conscious mice called Echo2Pheno, an automatic statistical learning workflow for analyzing and interpreting high-throughput non-anesthetized transthoracic murine echocardiographic images in the presence of genetic knockouts. Echo2Pheno comprises a neural network module for echocardiographic image analysis and phenotypic measurements, including a statistical hypothesis-testing framework for assessing phenotypic differences between populations. Using 2159 images of 16 different knockout mouse strains of the German Mouse Clinic, Echo2Pheno accurately confirms known cardiovascular genotype-phenotype relationships (e.g., Dystrophin) and discovers novel genes (e.g., CCR4-NOT transcription complex subunit 6-like, Cnot6l, and synaptotagmin-like protein 4, Sytl4), which cause altered cardiovascular phenotypes, as verified by H&E-stained histological images. Echo2Pheno provides an important step toward automatic end-to-end learning for linking echocardiographic readouts to cardiovascular phenotypes of interest in conscious mice.
AU  - Bukas, C.
AU  - Galter, I.
AU  - da Silva Buttkus, P.
AU  - Fuchs, H.
AU  - Maier, H.
AU  - Gailus-Durner, V.
AU  - Müller, C.L.
AU  - Hrabě de Angelis, M.
AU  - Piraud, M.
AU  - Spielmann, N.
C1  - 67903
C2  - 54381
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 200-215
TI  - Echo2Pheno: A deep-learning application to uncover echocardiographic phenotypes in conscious mice.
JO  - Mamm. Genome
VL  - 34
IS  - 2
PB  - Springer
PY  - 2023
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Rare diseases (RDs) are a challenge for medicine due to their heterogeneous clinical manifestations and low prevalence. There is a lack of specific treatments and only a few hundred of the approximately 7,000 RDs have an approved regime. Rapid technological development in genome sequencing enables the mass identification of potential candidates that in their mutated form could trigger diseases but are often not confirmed to be causal. Knockout (KO) mouse models are essential to understand the causality of genes by allowing highly standardized research into the pathogenesis of diseases. The German Mouse Clinic (GMC) is one of the pioneers in mouse research and successfully uses (preclinical) data obtained from single-gene KO mutants for research into monogenic RDs. As part of the International Mouse Phenotyping Consortium (IMPC) and INFRAFRONTIER, the pan-European consortium for modeling human diseases, the GMC expands these preclinical data toward global collaborative approaches with researchers, clinicians, and patient groups.Here, we highlight proprietary genes that when deleted mimic clinical phenotypes associated with known RD targets (Nacc1, Bach2, Klotho alpha). We focus on recognized RD genes with no pre-existing KO mouse models (Kansl1l, Acsf3, Pcdhgb2, Rabgap1, Cox7a2) which highlight novel phenotypes capable of optimizing clinical diagnosis. In addition, we present genes with intriguing phenotypic data (Zdhhc5, Wsb2) that are not presently associated with known human RDs.This report provides comprehensive evidence for genes that when deleted cause differences in the KO mouse across multiple organs, providing a huge translational potential for further understanding monogenic RDs and their clinical spectrum. Genetic KO studies in mice are valuable to further explore the underlying physiological mechanisms and their overall therapeutic potential.
AU  - da Silva Buttkus, P.
AU  - Spielmann, N.
AU  - Klein-Rodewald, T.
AU  - Schütt, C.
AU  - Aguilar-Pimentel, J.A.
AU  - Amarie, O.V.
AU  - Becker, L.
AU  - Calzada-Wack, J.
AU  - Garrett, L.
AU  - Gerlini, R.
AU  - Kraiger, M.
AU  - Leuchtenberger, S.
AU  - Östereicher, M.A.
AU  - Rathkolb, B.
AU  - Sanz-Moreno, A.
AU  - Stoeger, C.
AU  - Hölter, S.M.
AU  - Seisenberger, C.
AU  - Marschall, S.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
C1  - 67815
C2  - 54293
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 244-261
TI  - Knockout mouse models as a resource for the study of rare diseases.
JO  - Mamm. Genome
VL  - 34
IS  - 2
PB  - Springer
PY  - 2023
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Systemic-to-pulmonary shunt malfunction contributes to morbidity in children with complex congenital heart disease after palliative procedure. Neointimal hyperplasia might play a role in the pathogenesis increasing risk for shunt obstruction. The aim was to evaluate the role of epidermal growth factor receptor (EGFR) and matrix-metalloproteinase 9 (MMP-9) in the formation of neointimal within shunts. Immunohistochemistry was performed with anti-EGFR and anti-MMP-9 on shunts removed at follow-up palliative or corrective procedure. Whole-genome single-nucleotide polymorphisms genotyping was performed on DNA extracted from patients´ blood samples and allele frequencies were compared between the group of patients with shunts displaying severe stenosis (≥ 40% of lumen) and the remaining group. Immunohistochemistry detected EGFR and MMP-9 in 24 of 31 shunts, located mainly in the luminal area. Cross-sectional area of EGFR and MMP-9 measured in median 0.19 mm2 (IQR 0.1-0.3 mm2) and 0.04 mm2 (IQR 0.03-0.09 mm2), respectively, and correlated positively with the area of neointimal measured on histology (r = 0.729, p < 0.001 and r = 0.0479, p = 0.018, respectively). There was a trend of inverse correlation between the dose of acetylsalicylic acid and the degree of EGFR, but not MMP-9, expression within neointima. Certain alleles in epidermal growth factor (EGF) and tissue inhibitor of metalloproteinases 1 (TIMP-1) were associated with increased stenosis and neointimal hyperplasia within shunts. EGFR and MMP-9 contribute to neointimal proliferation in SP shunts of children with complex cyanotic heart disease. SP shunts from patients carrying certain risk alleles in the genes encoding for EGF and TIMP-1 displayed increased neointima.
AU  - Kottmann, P.*
AU  - Eildermann, K.*
AU  - Murthi, S.R.*
AU  - Cleuziou, J.*
AU  - Lemmer, J.*
AU  - Vitanova, K.*
AU  - von Stumm, M.*
AU  - Lehmann, L.*
AU  - Hörer, J.*
AU  - Ewert, P.*
AU  - Sigler, M.*
AU  - Lange, R.*
AU  - Lahm, H.*
AU  - Dreßen, M.*
AU  - Lichtner, P.
AU  - Wolf, C.M.*
C1  - 67561
C2  - 53591
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 285-297
TI  - EGFR and MMP-9 are associated with neointimal hyperplasia in systemic-to-pulmonary shunts in children with complex cyanotic heart disease.
JO  - Mamm. Genome
VL  - 34
IS  - 2
PB  - Springer
PY  - 2023
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Cardiovascular diseases cause a high mortality rate worldwide and represent a major burden for health care systems. Experimental rodent models play a central role in cardiovascular disease research by effectively simulating human cardiovascular diseases. Using mice, the International Mouse Phenotyping Consortium (IMPC) aims to target each protein-coding gene and phenotype multiple organ systems in single-gene knockout models by a global network of mouse clinics. In this review, we summarize the current advances of the IMPC in cardiac research and describe in detail the diagnostic requirements of high-throughput electrocardiography and transthoracic echocardiography capable of detecting cardiac arrhythmias and cardiomyopathies in mice. Beyond that, we are linking metabolism to the heart and describing phenotypes that emerge in a set of known genes, when knocked out in mice, such as the leptin receptor (Lepr), leptin (Lep), and Bardet–Biedl syndrome 5 (Bbs5). Furthermore, we are presenting not yet associated loss-of-function genes affecting both, metabolism and the cardiovascular system, such as the RING finger protein 10 (Rfn10), F-box protein 38 (Fbxo38), and Dipeptidyl peptidase 8 (Dpp8). These extensive high-throughput data from IMPC mice provide a promising opportunity to explore genetics causing metabolic heart disease with an important translational approach.
AU  - Lindovsky, J.*
AU  - Nichtová, Z.*
AU  - Dragano, N.R.V.
AU  - Pajuelo Reguera, D.*
AU  - Prochazka, J.*
AU  - Fuchs, H.
AU  - Marschall, S.
AU  - Gailus-Durner, V.
AU  - Sedlacek, R.*
AU  - Hrabě de Angelis, M.
AU  - Rozman, J.*
AU  - Spielmann, N.
C1  - 68516
C2  - 54685
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 107-122
TI  - A review of standardized high-throughput cardiovascular phenotyping with a link to metabolism in mice.
JO  - Mamm. Genome
VL  - 34
IS  - 2
PB  - Springer
PY  - 2023
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice.
AU  - Oestereicher, M.A.
AU  - Wotton, J.M.*
AU  - Ayabe, S.*
AU  - Bou About, G.*
AU  - Cheng, T.K.*
AU  - Choi, J.H.*
AU  - Clary, D.*
AU  - Dew, E.M.*
AU  - Elfertak, L.*
AU  - Guimond, A.*
AU  - Haseli Mashhadi, H.*
AU  - Heaney, J.D.*
AU  - Kelsey, L.*
AU  - Keskivali-Bond, P.*
AU  - Lopez Gomez, F.*
AU  - Marschall, S.
AU  - McFarland, M.*
AU  - Meziane, H.*
AU  - Munoz Fuentes, V.*
AU  - Nam, K.H.*
AU  - Nichtová, Z.*
AU  - Pimm, D.*
AU  - Bower, L.*
AU  - Prochazka, J.*
AU  - Rozman, J.*
AU  - Santos, L.*
AU  - Stewart, M.*
AU  - Tanaka, N.*
AU  - Ward, C.S.*
AU  - Willett, A.M.E.*
AU  - Wilson, R.*
AU  - Braun, R.E.*
AU  - Dickinson, M.E.*
AU  - Flenniken, A.M.*
AU  - Herault, Y.*
AU  - Lloyd, K.C.K.*
AU  - Mallon, A.M.*
AU  - McKerlie, C.*
AU  - Murray, S.A.*
AU  - Nutter, L.M.J.*
AU  - Sedlacek, R.*
AU  - Seong, J.K.*
AU  - Sorg, T.*
AU  - Tamura, M.*
AU  - Wells, S.*
AU  - Schneltzer, E.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - White, J.K.*
AU  - Spielmann, N.
C1  - 67835
C2  - 54313
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 180-199
TI  - Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice.
JO  - Mamm. Genome
VL  - 34
IS  - 2
PB  - Springer
PY  - 2023
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Rozman, J.*
AU  - Yang, Z.*
AU  - Spielmann, N.
C1  - 67821
C2  - 54299
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 105-106
TI  - Introduction to Mammalian Genome special issue: Cardiovascular disease in the Mammalian Genome.
JO  - Mamm. Genome
VL  - 34
IS  - 2
PB  - Springer
PY  - 2023
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Neuropsychiatric diseases (NPD) represent a significant global disease burden necessitating innovative approaches to pathogenic understanding, biomarker identification and therapeutic strategy. Emerging evidence implicates heart/brain axis malfunction in NPD etiology, particularly via the autonomic nervous system (ANS) and brain central autonomic network (CAN) interaction. This heart/brain inter-relationship harbors potentially novel NPD diagnosis and treatment avenues. Nevertheless, the lack of multidisciplinary clinical approaches as well as a limited appreciation of molecular underpinnings has stymied progress. Large-scale preclinical multi-systemic functional data can therefore provide supplementary insight into CAN and ANS interaction. We here present an overview of the heart/brain axis in NPD and establish a unique rationale for utilizing a preclinical cardiovascular disease risk gene set to glean insights into heart/brain axis control in NPD. With a top-down approach focusing on genes influencing electrocardiogram ANS function, we combined hierarchical clustering of corresponding regional CAN expression data and functional enrichment analysis to reveal known and novel molecular insights into CAN and NPD. Through 'support vector machine' inquiries for classification and literature validation, we further pinpointed the top 32 genes highly expressed in CAN brain structures altering both heart rate/heart rate variability (HRV) and behavior. Our observations underscore the potential of HRV/hyperactivity behavior as endophenotypes for multimodal disease biomarker identification to index aberrant executive brain functioning with relevance for NPD. This work heralds the potential of large-scale preclinical functional genetic data for understanding CAN/ANS control and introduces a stepwise design leveraging preclinical data to unearth novel heart/brain axis control genes in NPD.
AU  - Garrett, L.
AU  - Trümbach, D.
AU  - Spielmann, N.
AU  - Wurst, W.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Hölter, S.M.
C1  - 67055
C2  - 53430
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 331-350
TI  - A rationale for considering heart/brain axis control in neuropsychiatric disease.
JO  - Mamm. Genome
VL  - 34
IS  - 2
PB  - Springer
PY  - 2022
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Ubiquinol cytochrome c reductase hinge protein (UQCRH) is required for the electron transfer between cytochrome c1 and c of the mitochondrial cytochrome bc1 Complex (CIII). A two-exon deletion in the human UQCRH gene has recently been identified as the cause for a rare familial mitochondrial disorder. Deletion of the corresponding gene in the mouse (Uqcrh-KO) resulted in striking biochemical and clinical similarities including impairment of CIII, failure to thrive, elevated blood glucose levels, and early death. Here, we set out to test how global ablation of the murine Uqcrh affects cardiac morphology and contractility, and bioenergetics. Hearts from Uqcrh-KO mutant mice appeared macroscopically considerably smaller compared to wildtype littermate controls despite similar geometries as confirmed by transthoracic echocardiography (TTE). Relating TTE-assessed heart to body mass revealed the development of subtle cardiac enlargement, but histopathological analysis showed no excess collagen deposition. Nonetheless, Uqcrh-KO hearts developed pronounced contractile dysfunction. To assess mitochondrial functions, we used the high-resolution respirometer NextGen-O2k allowing measurement of mitochondrial respiratory capacity through the electron transfer system (ETS) simultaneously with the redox state of ETS-reactive coenzyme Q (Q), or production of reactive oxygen species (ROS). Compared to wildtype littermate controls, we found decreased mitochondrial respiratory capacity and more reduced Q in Uqcrh-KO, indicative for an impaired ETS. Yet, mitochondrial ROS production was not generally increased. Taken together, our data suggest that Uqcrh-KO leads to cardiac contractile dysfunction at 9 weeks of age, which is associated with impaired bioenergetics but not with mitochondrial ROS production. Graphical abstract: Global ablation of the Uqcrh gene results in functional impairment of CIII associated with metabolic dysfunction and postnatal developmental arrest immediately after weaning from the mother. Uqcrh-KO mice show dramatically elevated blood glucose levels and decreased ability of isolated cardiac mitochondria to consume oxygen (O2). Impaired development (failure to thrive) after weaning manifests as a deficiency in the gain of body mass and growth of internal organ including the heart. The relative heart mass seemingly increases when organ mass calculated from transthoracic echocardiography (TTE) is normalized to body mass. Notably, the heart shows no signs of collagen deposition, yet does develop a contractile dysfunction reflected by a decrease in ejection fraction and fractional shortening. [Figure not available: see fulltext.].
AU  - Spielmann, N.
AU  - Schenkl, C.*
AU  - Komlódi, T.*
AU  - da Silva Buttkus, P.
AU  - Heyne, E.*
AU  - Rohde, J.
AU  - Amarie, O.V.
AU  - Rathkolb, B.
AU  - Gnaiger, E.*
AU  - Doenst, T.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Szibor, M.*
C1  - 67105
C2  - 53482
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 229-243
TI  - Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction.
JO  - Mamm. Genome
VL  - 34
IS  - 2
PB  - Springer
PY  - 2022
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45. Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.
AU  - Biagosch, C.
AU  - Vidali, S.
AU  - Faerberboeck, M.
AU  - Hensler, S.
AU  - Becker, L.
AU  - Amarie, O.V.
AU  - Aguilar-Pimentel, J.A.
AU  - Garrett, L.
AU  - Klein-Rodewald, T.
AU  - Rathkolb, B.
AU  - Zanuttigh, E.
AU  - Calzada-Wack, J.
AU  - da Silva Buttkus, P.
AU  - Rozman, J.
AU  - Treise, I.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Janik, D.
AU  - Wurst, W.
AU  - Mayr, J.A.*
AU  - Klopstock, T.*
AU  - Meitinger, T.
AU  - Prokisch, H.
AU  - Iuso, A.
C1  - 62149
C2  - 50468
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 332-349
TI  - A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse.
JO  - Mamm. Genome
VL  - 32
IS  - 5
PB  - Springer
PY  - 2021
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Improving reproducibility and replicability in preclinical research is a widely discussed and pertinent topic, especially regarding ethical responsibility in animal research. INFRAFRONTIER, the European Research Infrastructure for the generation, phenotyping, archiving, and distribution of model mammalian genomes, is addressing this issue by developing internal quality principles for its different service areas, that provides a quality framework for its operational activities. This article introduces the INFRAFRONTIER Quality Principles in Systemic Phenotyping of genetically altered mouse models. A total of 11 key principles are included, ranging from general requirements for compliance with guidelines on animal testing, to the need for well-trained personnel and more specific standards such as the exchange of reference lines. Recently established requirements such as the provision of FAIR (Findable, Accessible, Interoperable, Reusable) data are also addressed. For each quality principle, we have outlined the specific context, requirements, further recommendations, and key references.
AU  - Ehlich, H.*
AU  - Cater, H.L.*
AU  - Flenniken, A.M.*
AU  - Goncalves Da Cruz, I.*
AU  - Mura, A.M.*
AU  - Ntafis, V.*
AU  - Raess, M.*
AU  - Selloum, M.*
AU  - Stoeger, C.
AU  - Suchanova, S.*
AU  - Vuolteenaho, R.*
AU  - Brown, S.D.M.*
AU  - Hérault, Y.*
AU  - Hinttala, R.*
AU  - Hrabě de Angelis, M.
AU  - Kollias, G.*
AU  - Kontoyiannis, D.L.*
AU  - Malissen, B.*
AU  - McKerlie, C.*
AU  - Sedláček, R.*
AU  - Wells, S.E.*
AU  - Zarubica, A.*
AU  - Rozman, J.*
AU  - Sorg, T.*
C1  - 62734
C2  - 51038
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - INFRAFRONTIER quality principles in systemic phenotyping.
JO  - Mamm. Genome
PB  - Springer
PY  - 2021
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Beckers, J.
AU  - Teperino, R.
AU  - Hérault, Y.*
AU  - Hrabě de Angelis, M.
C1  - 59648
C2  - 48894
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Introduction to mammalian genome special issue: Epigenetics.
JO  - Mamm. Genome
PB  - Springer
PY  - 2020
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Cellular heterogeneity is revolutionizing the way to study, monitor and dissect complex diseases. This has been possible with the technological and computational advances associated to single-cell genomics and epigenomics. Deeper understanding of cell-to-cell variation and its impact on tissue function will open new avenues for early disease detection, accurate diagnosis and personalized treatments, all together leading to the next generation of health care. This review focuses on the recent discoveries that single-cell genomics and epigenomics have facilitated in the context of human health. It highlights the potential of single-cell omics to further advance the development of personalized treatments and precision medicine in cancer, diabetes and chronic age-related diseases. The promise of single-cell technologies to generate new insights about the differences in function between individual cells is just emerging, and it is paving the way for identifying biomarkers and novel therapeutic targets to tackle age, complex diseases and understand the effect of life style interventions and environmental factors.
AU  - Kamies, R.
AU  - Martinez Jimenez, C.P.
C1  - 58927
C2  - 48640
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 170-180
TI  - Advances of single-cell genomics and epigenomics in human disease: Where are we now?
JO  - Mamm. Genome
VL  - 31
IS  - 5-6
PB  - Springer
PY  - 2020
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Nutritional constraints including not only caloric restriction or protein deficiency, but also energy-dense diets affect metabolic health and frequently lead to obesity and insulin resistance, as well as glucose intolerance and type 2 diabetes. The effects of these environmental factors are often mediated via epigenetic modifiers that target the expression of metabolic genes. More recently, it was discovered that such parentally acquired metabolic changes can alter the metabolic health of the filial and grand-filial generations. In mammals, this epigenetic inheritance can either follow an intergenerational or transgenerational mode of inheritance. In the case of intergenerational inheritance, epimutations established in gametes persist through the first round of epigenetic reprogramming occurring during preimplantation development. For transgenerational inheritance, epimutations persist additionally throughout the reprogramming that occurs during germ cell development later in embryogenesis. Differentially expressed transcripts, genomic cytosine methylations, and several chemical modifications of histones are prime candidates for tangible marks which may serve as epimutations in inter- and transgenerational inheritance and which are currently being investigated experimentally. We review, here, the current literature in support of epigenetic inheritance of metabolic traits caused by nutritional constraints and potential mechanisms in man and in rodent model systems.
AU  - Kaspar, D.
AU  - Hastreiter, S.
AU  - Irmler, M.
AU  - Hrabě de Angelis, M.
AU  - Beckers, J.
C1  - 58998
C2  - 48448
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 119–133
TI  - Nutrition and its role in epigenetic inheritance of obesity and diabetes across generations.
JO  - Mamm. Genome
VL  - 31
PB  - Springer
PY  - 2020
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads.
AU  - Kollmus, H.*
AU  - Fuchs, H.
AU  - Lengger, C.
AU  - Haselimashhadi, H.*
AU  - Bogue, M.A.*
AU  - Östereicher, M.A.
AU  - Horsch, M.
AU  - Adler, T.
AU  - Aguilar-Pimentel, J.A.
AU  - Amarie, O.V.
AU  - Becker, L.
AU  - Beckers, J.
AU  - Calzada-Wack, J.
AU  - Garrett, L.
AU  - Hans, W.
AU  - Hölter, S.M.
AU  - Klein-Rodewald, T.
AU  - Maier, H.
AU  - Mayer-Kuckuk, P.
AU  - Miller, G.
AU  - Moreth, K.
AU  - Neff, F.
AU  - Rathkolb, B.
AU  - Rácz, I.
AU  - Rozman, J.
AU  - Spielmann, N.
AU  - Treise, I.
AU  - Busch, D.H.
AU  - Graw, J.
AU  - Klopstock, T.*
AU  - Wolf, E.*
AU  - Wurst, W.
AU  - Yildirim, A.Ö.
AU  - Mason, J.*
AU  - Torres, A.*
AU  - Balling, R.*
AU  - Mehaan, T.*
AU  - Gailus-Durner, V.
AU  - Schughart, K.*
AU  - Hrabě de Angelis, M.
C1  - 58774
C2  - 48305
SP  - 30-48
TI  - A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes.
JO  - Mamm. Genome
VL  - 31
IS  - 1-2
PY  - 2020
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Design and production of genetically engineered mouse strains by individual research laboratories, research teams, large-scale consortia, and the biopharmaceutical industry have magnified the need for qualified personnel to identify, annotate, and validate (phenotype) these potentially new mouse models of human disease. The PATHBIO project has been recently established and funded by the European Union's ERASMUS+ Knowledge Alliance program to address the current shortfall in formally trained personnel. A series of teaching workshops will be given by experts on anatomy, histology, embryology, imaging, and comparative pathology to increase the availability of individuals with formal training to contribute to this important niche of Europe's biomedical research enterprise. These didactic and hands-on workshops are organized into three modules: (1) embryology, anatomy, histology, and the anatomical basis of imaging, (2) image-based phenotyping, and (3) pathology. The workshops are open to all levels of participants from recent graduates to Ph.D., M.D., and veterinary scientists. Participation is available on a competitive basis at no cost for attending. The first series of Workshop Modules was held in 2019 and these will continue for the next 2 years.
AU  - Ruberte, J.*
AU  - Schofield, P.N.*
AU  - Brakebusch, C.*
AU  - Vogel, P.*
AU  - Herault, Y.*
AU  - Gracia, G.*
AU  - McKerlie, C.*
AU  - Hrabě de Angelis, M.
AU  - Hagn, M.
AU  - Sundberg, J.P.*
C1  - 58704
C2  - 48253
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 49-53
TI  - PATHBIO: An international training program for precision mouse phenotyping.
JO  - Mamm. Genome
VL  - 31
IS  - 1-2
PB  - Springer
PY  - 2020
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Thought to be directly and uniquely dependent from genotypes, the ontogeny of individual phenotypes is much more complicated. Individual genetics, environmental exposures, and their interaction are the three main determinants of individual's phenotype. This picture has been further complicated a decade ago when the Lamarckian theory of acquired inheritance has been rekindled with the discovery of epigenetic inheritance, according to which acquired phenotypes can be transmitted through fertilization and affect phenotypes across generations. The results of Genome-Wide Association Studies have also highlighted a big degree of missing heritability in genetics and have provided hints that not only acquired phenotypes, but also individual's genotypes affect phenotypes intergenerationally through indirect genetic effects. Here, we review available examples of indirect genetic effects in mammals, what is known of the underlying molecular mechanisms and their potential impact for our understanding of missing heritability, phenotypic variation. and individual disease risk.
AU  - Tomar, A.
AU  - Teperino, R.
C1  - 59354
C2  - 48743
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 146–156
TI  - Genetic control of non-genetic inheritance in mammals: state-of-the-art and perspectives.
JO  - Mamm. Genome
VL  - 31
PB  - Springer
PY  - 2020
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - DNA double-strand breaks (DSBs) are produced intentionally by RNA-guided nucleases to achieve genome editing through DSB repair. These breaks are repaired by one of two main repair pathways, classic non-homologous end joining (c-NHEJ) and homology-directed repair (HDR), the latter being restricted to the S/G2 phases of the cell cycle and notably less frequent. Precise genome editing applications rely on HDR, with the abundant c-NHEJ formed mutations presenting a barrier to achieving high rates of precise sequence modifications. Here, we give an overview of HDR- and c-NHEJ-mediated DSB repair in gene editing and summarize the current efforts to promote HDR over c-NHEJ.
AU  - Danner, E.*
AU  - Bashir, S.*
AU  - Yumlu, S.*
AU  - Wurst, W.
AU  - Wefers, B.
AU  - Kuehn, R.*
C1  - 51829
C2  - 43392
CY  - New York
SP  - 262-274
TI  - Control of gene editing by manipulation of DNA repair mechanisms.
JO  - Mamm. Genome
VL  - 28
IS  - 7-8
PB  - Springer
PY  - 2017
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - We performed exome sequencing for mutation discovery of an ENU (N-ethyl-N-nitrosourea)-derived mouse model characterized by significant elevated plasma alkaline phosphatase (ALP) activities in female and male mutant mice, originally named BAP014 (bone screen alkaline phosphatase #14). We identified a novel loss-of-function mutation within the Fam46a (family with sequence similarity 46, member A) gene (NM_001160378.1:c.469G>T, NP_001153850.1:p.Glu157*). Heterozygous mice of this mouse line (renamed Fam46a (E157*Mhda)) had significantly high ALP activities and apparently no other differences in morphology compared to wild-type mice. In contrast, homozygous Fam46a (E157*Mhda) mice showed severe morphological and skeletal abnormalities including short stature along with limb, rib, pelvis, and skull deformities with minimal trabecular bone and reduced cortical bone thickness in long bones. ALP activities of homozygous mutants were almost two-fold higher than in heterozygous mice. Fam46a is weakly expressed in most adult and embryonic tissues with a strong expression in mineralized tissues as calvaria and femur. The FAM46A protein is computationally predicted as a new member of the superfamily of nucleotidyltransferase fold proteins, but little is known about its function. Fam46a (E157*Mhda) mice are the first mouse model for a mutation within the Fam46a gene.
AU  - Diener, S.
AU  - Bayer, S.
AU  - Sabrautzki, S.
AU  - Wieland, T.
AU  - Mentrup, B.*
AU  - Przemeck, G.K.H.
AU  - Rathkolb, B.
AU  - Graf, E.
AU  - Hans, W.
AU  - Fuchs, H.
AU  - Horsch, M.
AU  - Schwarzmayr, T.
AU  - Wolf, E.*
AU  - Klopocki, E.*
AU  - Jakob, F.*
AU  - Strom, T.M.
AU  - Hrabě de Angelis, M.
AU  - Lorenz-Depiereux, B.
C1  - 47752
C2  - 39472
CY  - New York
SP  - 111-121
TI  - Exome sequencing identifies a nonsense mutation in Fam46a associated with bone abnormalities in a new mouse model for skeletal dysplasia.
JO  - Mamm. Genome
VL  - 27
IS  - 3-4
PB  - Springer
PY  - 2016
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Ageing research and more generally the study of the functional basis of human diseases profit enormously from the large-scale approaches and resources in mouse functional genomics: systematic targeted mutation of the mouse genome, systemic phenotyping in mouse clinics, and the archiving and distribution of the mouse resources in public repositories. INFRAFRONTIER, the European research infrastructure for the development, systemic phenotyping, archiving and distribution of mammalian models, offers access to sustainable mouse resources for biomedical research. INFRAFRONTIER promotes the global sharing of high-quality resources and data and thus contributes to data reproducibility and animal welfare. INFRAFRONTIER puts great effort into international standardisation and quality control and into technology development to improve and expand experimental protocols, reduce the use of animals in research and increase the reproducibility of results. In concert with the research community and the International Mouse Phenotyping Consortium (IMPC), INFRAFRONTIER is currently developing new pilot platforms and services for the research on ageing and age-related diseases.
AU  - Raess, M.*
AU  - de Castro, A.A.*
AU  - Gailus-Durner, V.
AU  - Fessele, S.*
AU  - Hrabě de Angelis, M.
C1  - 48742
C2  - 41306
CY  - New York
SP  - 445-450
TI  - INFRAFRONTIER: A European resource for studying the functional basis of human disease.
JO  - Mamm. Genome
VL  - 27
IS  - 7-8
PB  - Springer
PY  - 2016
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Animal models resembling human mutations are valuable tools to research the features of complex human craniofacial syndromes. This is the first report on a viable dominant mouse model carrying a non-synonymous sequence variation within the endothelin receptor type A gene (Ednra c.386A>T, p.Tyr129Phe) derived by an ENU mutagenesis program. The identical amino acid substitution was reported recently as disease causing in three individuals with the mandibulofacial dysostosis with alopecia (MFDA, OMIM 616367) syndrome. We performed standardized phenotyping of wild-type, heterozygous, and homozygous Ednra (Y129F) mice within the German Mouse Clinic. Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals. As observed in MFDA-affected individuals, mutant Ednra (Y129F) mice exhibit hearing impairment in line with strong abnormalities of the ossicles and further, reduction of some lung volumetric parameters. In general, heterozygous and homozygous mice demonstrated inter-individual diversity of expression of the craniofacial phenotypes as observed in MFDA patients but without showing any cleft palates, eyelid defects, or alopecia. Mutant Ednra (Y129F) mice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches and for further studies and analysis of impaired endothelin 1 (EDN1)-endothelin receptor type A (EDNRA) signaling. Above all, Ednra (Y129F) mice model the recently published human MFDA syndrome and may be helpful for further disease understanding and development of therapeutic interventions.
AU  - Sabrautzki, S.
AU  - Sandholzer, M.A.
AU  - Lorenz-Depiereux, B.
AU  - Brommage, R.
AU  - Przemeck, G.K.H.
AU  - Vargas Panesso, I.L.*
AU  - Vernaleken, A.*
AU  - Garrett, L.
AU  - Baron, K.*
AU  - Yildirim, A.Ö.
AU  - Rozman, J.
AU  - Rathkolb, B.
AU  - Gau, C.
AU  - Hans, W.
AU  - Hölter, S.M.
AU  - Marschall, S.
AU  - Stoeger, C.
AU  - Becker, L.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Klingenspor, M.*
AU  - Klopstock, T.*
AU  - Lengger, C.
AU  - Stefanie, L.
AU  - Wolf, E.*
AU  - Strom, T.M.
AU  - Wurst, W.
AU  - Hrabě de Angelis, M.
C1  - 49569
C2  - 30068
CY  - New York
SP  - 587-598
TI  - Viable EdnraY129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation.
JO  - Mamm. Genome
VL  - 27
IS  - 11
PB  - Springer
PY  - 2016
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Epigenetic inheritance (EI) of metabolic phenotypes via the paternal lineage has been shown in rodent models of diet-induced obesity (DIO). However, the factors involved in soma-to-germline information transfer remain elusive. Here, we address the role of alterations in insulin, leptin, and adiponectin levels for EI of metabolic phenotypes by treating C57BL/6NTac male mice (F0) with the synthetic glucocorticoid dexamethasone and generating offspring (F1) either by in vitro fertilization or by natural fecundation. Dexamethasone treatment slightly alters F0 body composition by increasing fat mass and decreasing lean mass, and significantly improves glucose tolerance. Moreover, it increases insulin and leptin levels and reduces adiponectin levels in F0 fathers as observed in mouse models of DIO. However, these paternal changes of metabolic hormones do not alter metabolic parameters, such as body weight, body composition and glucose homeostasis in male and female F1 mice even when these are challenged with a high-fat diet. Accordingly, sperm transcriptomes are not altered by dexamethasone treatment. Our results suggest that neither increased glucocorticoid, insulin, and leptin levels, nor decreased adiponectin levels in fathers are sufficient to confer soma-to-germline information transfer in EI of obesity via the paternal lineage.
AU  - Bönisch, C.
AU  - Irmler, M.
AU  - Brachthäuser, L.
AU  - Neff, F.
AU  - Bamberger, M.T.
AU  - Marschall, S.
AU  - Hrabě de Angelis, M.
AU  - Beckers, J.
C1  - 47534
C2  - 40657
CY  - New York
SP  - 17-28
TI  - Dexamethasone treatment alters insulin, leptin, and adiponectin levels in male mice as observed in DIO but does not lead to alterations of metabolic phenotypes in the offspring.
JO  - Mamm. Genome
VL  - 27
IS  - 1-2
PB  - Springer
PY  - 2015
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question, we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (χ (2) = 19.1, df = 2, p = 7.0 × 10(-5)). Further extensive phenotypic analyses suggest hyperactivity (p < 0.05) of DUF1220 mice and changes in gene expression levels of brain associated with distinct neurological functions and disease. Other changes that met statistical significance include an increase in plasma glucose concentration (as measured by area under the curve, AUC 0-30 and AUC 30-120) in male mutants, fasting glucose levels, reduce sodium levels in male mutants, increased levels of the liver functional indicator ALAT/GPT in males, levels of alkaline phosphatase (also an indicator of liver function), mean R and SR amplitude by electrocardiography, elevated IgG3 levels, a reduced ratio of CD4:CD8 cells, and a reduced frequency of T cells; though it should be noted that many of these differences are quite small and require further examination. The linking of DUF1220 loss to a hyperactive phenotype is consistent with separate findings in which DUF1220 over expression results in a down-regulation of mitochondrial function, and potentially suggests a role in developmental metabolism. Finally, the substantially reduced fecundity we observe associated with KO mice argues that the ancestral DUF1220 domain provides an important biological functionthat is critical to survivability and reproductive success.
AU  - Keeney, J.G.*
AU  - O'Bleness, M.S.*
AU  - Anderson, N.*
AU  - Davis, J.M.*
AU  - Arevalo, N.*
AU  - Busquet, N.*
AU  - Chick, W.*
AU  - Rozman, J.
AU  - Hölter, S.M.
AU  - Garrett, L.
AU  - Horsch, M.
AU  - German Mouse Clinic Consortium (Adler, T.
AU  - Aguilar-Pimentel, J.A.
AU  - Amarie, O.V.
AU  - Eickelberg, O.
AU  - Gailus-Durner, V.
AU  - Graw, J.
AU  - Hans, W.
AU  - Horsch, M.
AU  - Janik, D.
AU  - Neff, F.
AU  - Ollert, M.
AU  - Puk, O.
AU  - Rácz, I.
AU  - Rathkolb, B.
AU  - Stöger, T.
AU  - Yildirim, A.Ö.)
AU  - Beckers, J.
AU  - Wurst, W.
AU  - Klingenspor, M.
AU  - Restrepo, D.*
AU  - Sikela, J.M.*
AU  - Hrabě de Angelis, M.
C1  - 32550
C2  - 35126
CY  - New York
SP  - 33-42
TI  - Generation of mice lacking DUF1220 protein domains: Effects on fecundity and hyperactivity.
JO  - Mamm. Genome
VL  - 26
IS  - 1-2
PB  - Springer
PY  - 2015
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Large-scale systemic mouse phenotyping, as performed by mouse clinics for more than a decade, requires thousands of mice from a multitude of different mutant lines to be bred, individually tracked and subjected to phenotyping procedures according to a standardised schedule. All these efforts are typically organised in overlapping projects, running in parallel. In terms of logistics, data capture, data analysis, result visualisation and reporting, new challenges have emerged from such projects. These challenges could hardly be met with traditional methods such as pen & paper colony management, spreadsheet-based data management and manual data analysis. Hence, different Laboratory Information Management Systems (LIMS) have been developed in mouse clinics to facilitate or even enable mouse and data management in the described order of magnitude. This review shows that general principles of LIMS can be empirically deduced from LIMS used by different mouse clinics, although these have evolved differently. Supported by LIMS descriptions and lessons learned from seven mouse clinics, this review also shows that the unique LIMS environment in a particular facility strongly influences strategic LIMS decisions and LIMS development. As a major conclusion, this review states that there is no universal LIMS for the mouse research domain that fits all requirements. Still, empirically deduced general LIMS principles can serve as a master decision support template, which is provided as a hands-on tool for mouse research facilities looking for a LIMS.
AU  - Maier, H.
AU  - Schütt, C.
AU  - Steinkamp, R.
AU  - Hurt, A.
AU  - Schneltzer, E.
AU  - Gormanns, P.
AU  - Lengger, C.
AU  - Griffiths, M.*
AU  - Melvin, D.*
AU  - Agrawal, N.*
AU  - Alcantara, R.*
AU  - Evans, A.*
AU  - Gannon, D.*
AU  - Holroyd, S.*
AU  - Kipp, C.*
AU  - Raj, N. P.*
AU  - Richardson, D.*
AU  - Leblanc, S.*
AU  - Vasseur, L.*
AU  - Masuya, H.*
AU  - Kobayashi, K.*
AU  - Suzuki, T.*
AU  - Tanaka, N.*
AU  - Wakana, S.*
AU  - Walling, A.*
AU  - Clary, D.*
AU  - Gallegos, J.*
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Gailus-Durner, V.
C1  - 46419
C2  - 37513
SP  - 467-481
TI  - Principles and application of LIMS in mouse clinics.
JO  - Mamm. Genome
VL  - 26
IS  - 9-10
PY  - 2015
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - The International Knockout Mouse Consortium (IKMC; http://www.mousephenotype.org) has generated mutations in almost every protein-coding mouse gene and is completing the companion Cre driver resource to expand tissue-specific conditional mutagenesis. Accordingly, the IKMC has carried out high-throughput gene trapping and targeting producing conditional mutations in murine embryonic stem cells in more than 18,500 genes, from which at least 4900 mutant mouse lines have been established to date. This resource is currently being upgraded with more powerful tools, such as visualization and manipulation cassettes that can be easily introduced into IKMC alleles for multifaceted functional studies. In addition, we discuss how existing IKMC products can be used in combination with CRISPR technology to accelerate genome engineering projects. All information and materials from this extraordinary biological resource together with coordinated phenotyping efforts can be retrieved at www.mousephenotype.org. The comprehensive IKMC knockout resource in combination with an extensive set of modular gene cassettes will continue to enhance functional gene annotation in the future and solidify its impact on biomedical research.
AU  - Rosen, B.*
AU  - Schick, J.
AU  - Wurst, W.
C1  - 46786
C2  - 37817
SP  - 456-466
TI  - Beyond knockouts: The International Knockout Mouse Consortium delivers modular and evolving tools for investigating mammalian genes.
JO  - Mamm. Genome
VL  - 26
IS  - 9-10
PY  - 2015
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Metabolic phenotyping of genetically modified animals aims to detect new candidate genes and related metabolic pathways that result in dysfunctional energy balance regulation and predispose for diseases such as obesity or type 2 diabetes mellitus. In this review, we provide a comprehensive overview on the technologies available to monitor energy flux (food uptake, bomb calorimetry of feces and food, and indirect calorimetry) and body composition (qNMR, DXA, and MRI) in animal models for human diseases with a special focus on phenotyping methods established in genetically engineered mice. We use an energy flux model to illustrate the principles of energy allocation, describe methodological aspects how to monitor energy balance, and introduce strategies for data analysis and presentation.
AU  - Rozman, J.
AU  - Klingenspor, M.
AU  - Hrabě de Angelis, M.
C1  - 32117
C2  - 35125
CY  - New York
SP  - 497-507
TI  - A review of standardized metabolic phenotyping of animal models.
JO  - Mamm. Genome
VL  - 25
IS  - 9
PB  - Springer
PY  - 2014
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - The phenotyping of genetic mouse models for human disorders may greatly benefit from breath gas analysis as a noninvasive tool to identify metabolic alterations in mice. Phenotyping screens such as the German Mouse Clinic demand investigations in unrestrained mice. Therefore, we adapted a breath screen in which exhaled volatile organic compounds (VOCs) were online monitored by proton transfer reaction mass spectrometry (hs-PTR-MS). The source strength of VOCs was derived from the dynamics in the accumulation profile of exhaled VOCs of a single mouse in a respirometry chamber. A careful survey of the accumulation revealed alterations in the source strength due to confounders, e.g., urine and feces. Moreover changes in the source strength of humidity were triggered by changes in locomotor behavior as mice showed a typical behavioral pattern from activity to settling down in the course of subsequent accumulation profiles. We demonstrated that metabolic changes caused by a dietary intervention, e.g., after feeding a high-fat diet (HFD) a sample of 14 male mice, still resulted in a statistically significant shift in the source strength of exhaled VOCs. Applying a normalization which was derived from the distribution of the source strength of humidity and accounted for varying locomotor behaviors improved the shift. Hence, breath gas analysis may provide a noninvasive, fast access to monitor the metabolic adaptation of a mouse to alterations in energy balance due to overfeeding or fasting and dietary macronutrient composition as well as a high potential for systemic phenotyping of mouse mutants, intervention studies, and drug testing in mice.
AU  - Szymczak, W.
AU  - Rozman, J.
AU  - Höllriegl, V.
AU  - Kistler, M.
AU  - Keller, S.
AU  - Peters, D.
AU  - Kneipp, M.
AU  - Schulz, H.
AU  - Hoeschen, C.
AU  - Klingenspor, M.*
AU  - Hrabě de Angelis, M.
C1  - 28502
C2  - 33436
CY  - New York
SP  - 129-140
TI  - Online breath gas analysis in unrestrained mice by hs-PTR-MS.
JO  - Mamm. Genome
VL  - 25
IS  - 3-4
PB  - Springer
PY  - 2014
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Dual-energy X-ray absorption (DEXA) is commonly used to measure bone mineral density (BMD), bone mineral content (BMC), and body composition data (fat mass and lean mass) for phenotype assessment in mice. We were interested in the long-term development of BMD, BMC, lean mass, and fat mass of mice, also taking into account sex and genetic background. The dataset was used to analyze correlations among the different parameters. We analyzed males and females from inbred strains C3HeB/FeJ and C57BL/6J, starting from 42 until 528 days of age. To evaluate the effect of husbandry systems, we repeated a part of the study in a second facility with a different caging system. We also assessed different DEXA settings and repeatability of the scans. The results of this study were used to draw conclusions for the use of DEXA analysis in mouse phenotyping approaches.
AU  - Fuchs, H.
AU  - Gau, C.
AU  - Hans, W.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
C1  - 27742
C2  - 32798
SP  - 376-388
TI  - Long-term experiment to study the development, interaction and influencing factors of DEXA parameters.
JO  - Mamm. Genome
VL  - 24
IS  - 9-10
PB  - Springer
PY  - 2013
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Spectral domain optical coherence tomography (SD-OCT) has recently been established as a method for in vivo imaging of fundus and retina in the mouse. It enables more effective studies of retinal diseases including investigations of etiopathologic mechanisms. In order to learn more about longitudinal fundus development and to enable recognition of disease-associated irregularities, we performed confocal scanning laser ophthalmoscopy (cSLO) and SD-OCT measurements in the inbred strains C57BL/6J, C3HeB/FeJ, FVB/NCrl, BALB/cByJ, and 129S2/SvJ when they were between 2 and 6 months of age. In general, cSLO and SD-OCT data did not reveal sex-specific or unilateral differences. C3HeB/FeJ and FVB/NCrl mice showed diffuse choroidal dysplasia. Choroidal vein-like structures appeared as dark fundus stripes in C3HeB/FeJ. In FVB/NCrl, fundus fleck accumulation was found. In contrast, only minor time-dependent changes of fundus appearance were observed in C57BL/6J, BALB/cByJ, and 129S2/SvJ. This was also found for individual fundic main blood vessel patterns in all inbred strains. Vessel numbers varied between 6 and 13 in C57BL/6J. This was comparable in most cases. We further found that retinae were significantly thicker in C57BL/6J compared to the other strains. Total retinal thickness generally did not change between 2 and 6 months of age. As a conclusion, our results indicate lifelong pathologic processes in C3HeB/FeJ and FVB/NCrl that affect choroid and orbital tissues. Inbred strains with regular retinal development did not reveal major time-dependent variations of fundus appearance, blood vessel pattern, or retinal thickness. Consequently, progressive changes of these parameters are suitable indicators for pathologic outliers.
AU  - Puk, O.
AU  - Hrabě de Angelis, M.
AU  - Graw, J.
C1  - 24502
C2  - 31560
SP  - 198-205
TI  - Longitudinal fundus and retinal studies with SD-OCT: A comparison of five mouse inbred strains.
JO  - Mamm. Genome
VL  - 24
IS  - 5-6
PB  - Springer
PY  - 2013
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Scheimpflug imaging has recently been established for in vivo imaging of the anterior eye segment and quantitative determination of lens transparency in the mouse. This enables more effective investigations of cataract formation with the mouse model, including longitudinal studies. In order to enable recognition of disease-associated irregularities, we performed Scheimpflug measurements with the common laboratory inbred lines C57BL/6J, C3HeB/FeJ, FVB/NCrl, BALB/cByJ, and 129/SvJ in a period between 2 and 12 months of age. C57BL/6J mice showed lowest mean lens densities during the test period. Progressive cortical lens opacification was generally observed, with the earliest onset in C57BBL/6J, C3HeB/FeJ, and 129/SvJ, between 2 and 6 months after birth. Moreover, lenses of these inbred lines developed nuclear opacities. Calculated mean lens density significantly increased between 6 and 12 months of age in all inbred strains except 129/SvJ. Lens densities (and the corresponding standard deviations) of FVB/NCrl and 129/SvJ increased most likely because of differences in the genetic background. Albinism as confounder might be excluded since the albino Balb/cByJ mice are more similar to the C57BL/6J or C3Heb/FeJ mice. We further identified strain-specific anterior lens opacities (C57BL/6J) and cloudy corneal lesions (C57BL/6J, FVB/NCrl, and BALB/cByJ) at later stages. In conclusion, our results indicate that there are lifelong opacification processes in the mouse lens. The highest lens transparency and a dark coat color, which prevents interference from light reflections, make mice with the C57BL/6J background most suitable for cataract research by Scheimpflug imaging. We show that lens densitometry by Scheimpflug imaging in mouse eyes can resolve differences of less than 1 %, making it possible to detect differences in cataract development in different mouse strains, even if they are small.
AU  - Puk, O.
AU  - Hrabě de Angelis, M.
AU  - Graw, J.
C1  - 26580
C2  - 32281
SP  - 295-302
TI  - Lens density tracking in mice by Scheimpflug imaging.
JO  - Mamm. Genome
VL  - 24
IS  - 7-8
PB  - Springer
PY  - 2013
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - βB2-crystallin (gene symbol: Crybb2/CRYBB2) was first described as a structural protein of the ocular lens. This gene, however, is also expressed in several regions of the mammalian brain, although its function in this organ remains entirely unknown. To unravel some aspects of its function in the brain, we combined behavioral, neuroanatomical, and physiological analyses in a novel Crybb2 mouse mutant, O377. Behavioral tests with male O377 mutants revealed altered sensorimotor gating, suggesting modified neuronal functions. Since these mouse mutants also displayed reduced hippocampal size, we concentrated further investigations on the hippocampus. Free intracellular Ca2+ levels were increased and apoptosis was enhanced in the hippocampus of O377 mutants. Moreover, the expression of the gene encoding calpain 3 (gene symbol Capn3) was elevated and the expression of genes coding for the NMDA receptor subunits was downregulated. Additionally, the number of parvalbumin-positive interneurons was decreased in the hippocampus but not in the cortex of the mutants. High-speed voltage-sensitive dye imaging demonstrated an increased translation of input-to-output neuronal activity in the dentate gyrus of this Crybb2 mutant. These results point to an important function of βB2-crystallin in the hippocampal network. They indicate pleiotropic effects of mutations in the Crybb2 gene, which previously had been considered to be specific to the ocular lens. Moreover, our results are the first to demonstrate that βB2-crystallin has a role in hippocampal function and behavioral phenotypes. This model can now be further explored by future experiments.
AU  - Sun, M.
AU  - Hölter, S.M.
AU  - Stepan, J.*
AU  - Garrett, L.
AU  - Genius, J.*
AU  - Kremmer, E.
AU  - Hrabě de Angelis, M.
AU  - Wurst, W.
AU  - Lie, D.C.
AU  - Bally-Cuif, L.
AU  - Eder, M.*
AU  - Rujescu, D.*
AU  - Graw, J.
C1  - 27743
C2  - 32799
SP  - 333-348
TI  - Crybb2 coding for βB2-crystallin affects sensorimotor gating and hippocampal function.
JO  - Mamm. Genome
VL  - 24
IS  - 9-10
PB  - Springer
PY  - 2013
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Two large-scale phenotyping efforts, the European Mouse Disease Clinic (EUMODIC) and the Wellcome Trust Sanger Institute Mouse Genetics Project (SANGER-MGP), started during the late 2000s with the aim to deliver a comprehensive assessment of phenotypes or to screen for robust indicators of diseases in mouse mutants. They both took advantage of available mouse mutant lines but predominantly of the embryonic stem (ES) cells resources derived from the European Conditional Mouse Mutagenesis programme (EUCOMM) and the Knockout Mouse Project (KOMP) to produce and study 799 mouse models that were systematically analysed with a comprehensive set of physiological and behavioural paradigms. They captured more than 400 variables and an additional panel of metadata describing the conditions of the tests. All the data are now available through EuroPhenome database ( www.europhenome.org ) and the WTSI mouse portal ( http://www.sanger.ac.uk/mouseportal/ ), and the corresponding mouse lines are available through the European Mouse Mutant Archive (EMMA), the International Knockout Mouse Consortium (IKMC), or the Knockout Mouse Project (KOMP) Repository. Overall conclusions from both studies converged, with at least one phenotype scored in at least 80 % of the mutant lines. In addition, 57 % of the lines were viable, 13 % subviable, 30 % embryonic lethal, and 7 % displayed fertility impairments. These efforts provide an important underpinning for a future global programme that will undertake the complete functional annotation of the mammalian genome in the mouse model.
AU  - Ayadi, A.*
AU  - Birling, M.-C.*
AU  - Bottomley, J.*
AU  - Bussel, L.*
AU  - Fuchs, H.
AU  - Frayx, M.*
AU  - Gailus-Durner, V.
AU  - Greenaway, S.*
AU  - Houghton, R.*
AU  - Karp, N.*
AU  - Leblanc, S.*
AU  - Lengger, C.
AU  - Maier, H.
AU  - Mallon, A.-M.*
AU  - Marschall, S.
AU  - Melvin, D.*
AU  - Morgan, H.*
AU  - Pavlovic, G.*
AU  - Ryder, E.*
AU  - Skarnes, W.C.*
AU  - Selloum, M.*
AU  - Ramirez-Solis, R.*
AU  - Sorg, T.*
AU  - Teboul, L.*
AU  - Vasseur, L.*
AU  - Walling, A.*
AU  - Weaver, T.*
AU  - Wells, S.*
AU  - White, J.K.*
AU  - Bradley, A.*
AU  - Adams, D.J.*
AU  - Steel, K. P.*
AU  - Hrabě de Angelis, M.
AU  - Brown, S.D.*
AU  - Herault, Y.*
C1  - 10772
C2  - 30364
SP  - 600-610
TI  - Mouse large-scale phenotyping initiatives: Overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute mouse genetics project.
JO  - Mamm. Genome
VL  - 23
IS  - 9-10
PB  - Springer
PY  - 2012
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal ( www.knockoutmouse.org ) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.
AU  - Bradley, A.*
AU  - Anastassiadis, K.*
AU  - Ayadi, A.*
AU  - Battey, J.F.*
AU  - Bell, C.*
AU  - Birling, M.-C.*
AU  - Bottomley, J.*
AU  - Brown, S.D.*
AU  - Bürger, A.
AU  - Bult, C.J.*
AU  - Bushell, W.*
AU  - Collins, F.S.*
AU  - Desaintes, C.*
AU  - Doe, B.*
AU  - Economides, A.*
AU  - Eppig, J.T.*
AU  - Finnell, R.H.*
AU  - Fletcher, C.*
AU  - Fray, M.*
AU  - Frendewey, D.*
AU  - Friedel, R.H.
AU  - Grosveld, F.G.*
AU  - Hansen, J.
AU  - Herault, Y.*
AU  - Hicks, G.*
AU  - Hörlein, A.
AU  - Houghton, R.*
AU  - Hrabě de Angelis, M.
AU  - Huylebroeck, D.*
AU  - Iyer, V.*
AU  - de Jong, P.J.*
AU  - Kadin, J.A.*
AU  - Kaloff, C.
AU  - Kennedy, K.*
AU  - Koutsourakis, M.*
AU  - Lloyd, K.C.K.*
AU  - Marschall, S.
AU  - Mason, J.*
AU  - McKerlie, C.*
AU  - McLeod, M.P.*
AU  - von Melchner, H.*
AU  - Moore, M.*
AU  - Mujica, A.O.*
AU  - Nagy, A.*
AU  - Nefedov, M.*
AU  - Nutter, L.M.*
AU  - Pavlovic, G.*
AU  - Peterson, J.L.*
AU  - Pollock, J.*
AU  - Ramirez-Solis, R.*
AU  - Rancourt, D.E.*
AU  - Raspa, M.*
AU  - Remacle, J.E.*
AU  - Ringwald, M.*
AU  - Rosen, B.*
AU  - Rosenthal, N.*
AU  - Rossant, J.*
AU  - Ruiz Noppinger, P.*
AU  - Ryder, E.*
AU  - Schick, J.
AU  - Schnütgen, F.*
AU  - Schofield, P.*
AU  - Seisenberger, C.
AU  - Selloum, M.*
AU  - Simpson, E.M.*
AU  - Skarnes, W.C.*
AU  - Smedley, D.*
AU  - Stanford, W.L.*
AU  - Francis Stewart, A.*
AU  - Stone, K.*
AU  - Swan, K.*
AU  - Tadepally, H.*
AU  - Teboul, L.*
AU  - Tocchini-Valentini, G.P.*
AU  - Valenzuela, D.*
AU  - West, A.P.*
AU  - Yamamura, K.*
AU  - Yoshinaga, Y.*
AU  - Wurst, W.
C1  - 10524
C2  - 30307
SP  - 580-586
TI  - The mammalian gene function resource: The International Knockout Mouse Consortium.
JO  - Mamm. Genome
VL  - 23
IS  - 9-10
PB  - Springer
PY  - 2012
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.
AU  - Donahue, L. R.*
AU  - Hrabě de Angelis, M.
AU  - Hagn, M.
AU  - Franklin, C.*
AU  - Lloyd, K.C.K.*
AU  - Magnuson, T.*
AU  - McKerlie, C.*
AU  - Nakagata, N.*
AU  - Obata, Y.*
AU  - Read, S.*
AU  - Wurst, W.*
AU  - Hörlein, A.*
AU  - Davisson, M. T.*
C1  - 10758
C2  - 30362
SP  - 559-571
TI  - Centralized mouse repositories.
JO  - Mamm. Genome
VL  - 23
IS  - 9-10
PB  - Springer
PY  - 2012
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Under the label of the German Mouse Clinic (GMC), a concept has been developed and implemented that allows the better understanding of human diseases on the pathophysiological and molecular level. This includes better understanding of the crosstalk between different organs, pleiotropy of genes, and the systemic impact of envirotypes and drugs. In the GMC, experts from various fields of mouse genetics and physiology, in close collaboration with clinicians, work side by side under one roof. The GMC is an open-access platform for the scientific community by providing phenotypic analysis in bilateral collaborations ("bottom-up projects") and as a partner and driver in international large-scale biology projects ("top-down projects"). Furthermore, technology development is a major topic in the GMC. Innovative techniques for primary and secondary screens are developed and implemented into the phenotyping pipelines (e.g., detection of volatile organic compounds, VOCs).
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Neschen, S.
AU  - Adler, T.
AU  - Afonso, L.C.
AU  - Aguilar-Pimentel, J.A.
AU  - Becker, L.
AU  - Bohla, A.
AU  - Calzada-Wack, J.
AU  - Cohrs, C.M.
AU  - Dewert, A.
AU  - Fridrich, B.
AU  - Garrett, L.
AU  - Glasl, L.
AU  - Götz, A.
AU  - Hans, W.
AU  - Hölter, S.M.
AU  - Horsch, M.
AU  - Hurt, A.
AU  - Janas, E.
AU  - Janik, D.
AU  - Kahle-Stephan, M.*
AU  - Kistler, M.*
AU  - Klein-Rodewald, T.
AU  - Lengger, C.*
AU  - Ludwig, T.*
AU  - Maier, H.*
AU  - Marschall, S.
AU  - Micklich, K.
AU  - Möller, G.
AU  - Naton, B.
AU  - Prehn, C.
AU  - Puk, O.
AU  - Rácz, I.*
AU  - Räß, M.
AU  - Rathkolb, B.
AU  - Rozman, J.
AU  - Scheerer, M.
AU  - Schiller, E.
AU  - Schrewe, A.
AU  - Steinkamp, R.
AU  - Stoeger, C.
AU  - Sun, M.
AU  - Szymczak, W.
AU  - Treise, I.
AU  - Vargas Panesso, I.L.
AU  - Vernaleken, A.
AU  - Willershäuser, M.
AU  - Zimprich, A.
AU  - Zeh, R.M.
AU  - Adamski, J.
AU  - Beckers, J.
AU  - Bekeredjian, R.*
AU  - Busch, D.H.*
AU  - Eickelberg, O.
AU  - Favor, J.
AU  - Graw, J.
AU  - Höfler, H.
AU  - Hoeschen, C.
AU  - Katus, H.A.*
AU  - Klingenspor, M.*
AU  - Klopstock, T.*
AU  - Neff, F.
AU  - Ollert, M.*
AU  - Schulz, H.
AU  - Stöger, T.
AU  - Wolf, E.*
AU  - Wurst, W.
AU  - Yildirim, A.Ö.
AU  - Zimmer, A.*
AU  - Hrabě de Angelis, M.
C1  - 10697
C2  - 30424
SP  - 611-622
TI  - Innovations in phenotyping of mouse models in the German Mouse Clinic.
JO  - Mamm. Genome
VL  - 23
IS  - 9-10
PB  - Springer
PY  - 2012
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - The large-scale mutagenesis programmes underway around the world are generating thousands of novel GA mouse strains that need to be securely archived. In parallel with advances in mutagenesis, the procedures used to cryopreserve mouse stocks are being continually refined in order to keep pace with demand. Moreover, the construction of extensive research infrastructures for systematic phenotyping is fuelling demand for these novel strains of mice and new approaches to the distribution of frozen and unfrozen embryos and gametes are being developed in order to reduce the dependency on the transportation of live mice. This article highlights some contemporary techniques used to archive, rederive, and transport mouse strains around the world.
AU  - Guan, M.*
AU  - Marschall, S.
AU  - Raspa, M.*
AU  - Pickard, A.R.*
AU  - Fray, M.D.*
C1  - 10882
C2  - 30438
SP  - 572-579
TI  - Overview of new developments in and the future of cryopreservation in the laboratory mouse.
JO  - Mamm. Genome
VL  - 23
IS  - 9-10
PB  - Springer
PY  - 2012
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Metabolic bone disorders arise as primary diseases or may be secondary due to a multitude of organ malfunctions. Animal models are required to understand the molecular mechanisms responsible for the imbalances of bone metabolism in disturbed bone mineralization diseases. Here we present the isolation of mutant mouse models for metabolic bone diseases by phenotyping blood parameters that target bone turnover within the large-scale genome-wide Munich ENU Mutagenesis Project. A screening panel of three clinical parameters, also commonly used as biochemical markers in patients with metabolic bone diseases, was chosen. Total alkaline phosphatase activity and total calcium and inorganic phosphate levels in plasma samples of F1 offspring produced from ENU-mutagenized C3HeB/FeJ male mice were measured. Screening of 9,540 mice led to the identification of 257 phenodeviants of which 190 were tested by genetic confirmation crosses. Seventy-one new dominant mutant lines showing alterations of at least one of the biochemical parameters of interest were confirmed. Fifteen mutations among three genes (Phex, Casr, and Alpl) have been identified by positional-candidate gene approaches and one mutation of the Asgr1 gene, which was identified by next-generation sequencing. All new mutant mouse lines are offered as a resource for the scientific community.
AU  - Sabrautzki, S.
AU  - Rubio-Aliaga, I.
AU  - Hans, W.
AU  - Fuchs, H.
AU  - Rathkolb, B.*
AU  - Calzada-Wack, J.
AU  - Cohrs, C.M.
AU  - Klaften, M.
AU  - Seedorf, H.*
AU  - Eck, S.H.
AU  - Benet-Pagès, A.
AU  - Favor, J.
AU  - Esposito, I.
AU  - Strom, T.M.
AU  - Wolf, E.*
AU  - Lorenz-Depiereux, B.
AU  - Hrabě de Angelis, M.
C1  - 8325
C2  - 30058
SP  - 416-430
TI  - New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis.
JO  - Mamm. Genome
VL  - 23
IS  - 7-8
PB  - Springer
PY  - 2012
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Mice genetically engineered to express human FcRn are valuable models for the evaluation of therapeutic antibodies in the context of human FcRn in vivo. However, only limited clinical chemistry information on these mouse strains is available. Thus, we have compared 30 clinical chemical parameters of C57BL/6J wild-type mice, murine FcRn-knockout mice, and two human FcRn transgenic mouse strains expressing human FcRn in the absence of murine FcRn. Since FcRn-mediated recycling prevents albumin and IgG from intracellular degradation, significant differences for both proteins were observed in the murine FcRn-knockout mice. Mice lacking FcRn show lower IgG and albumin levels compared to wild-type mice. The most prominent differences in clinical chemical parameters can be explained by secondary effects of the altered albumin levels of murine FcRn-knockout mice on liver metabolism, as similar tendencies have been observed in analbuminemic Nagase rats and hypoalbuminemic human patients, showing an overall increased liver metabolism. Both human FcRn transgenic strains show clinical chemical parameters similar to those found for wild-type mice, with the exception of endogenous IgG levels, which are greatly reduced in these mice.
AU  - Stein, C.*
AU  - Kling, L.*
AU  - Proetzel, G.*
AU  - Roopenian, D.C.*
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
AU  - Rathkolb, B.
C1  - 7101
C2  - 29605
SP  - 259-269
TI  - Clinical chemistry of human FcRn transgenic mice.
JO  - Mamm. Genome
VL  - 23
IS  - 3-4
PB  - Springer
PY  - 2012
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Research on hematological disorders relies on suitable animal models. We retrospectively evaluated the use of the hematological parameters hematocrit (HCT), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red blood cell count (RBC), white blood cell count (WBC), and platelet count (PLT) in the phenotype-driven Munich N-ethyl-N-nitrosourea (ENU) mouse mutagenesis project as parameters for the generation of novel animal models for human diseases. The analysis was carried out on more than 16,000 G1 and G3 offspring of chemically mutagenized inbred C3H mice to detect dominant and recessive mutations leading to deviations in the levels of the chosen parameters. Identification of animals exhibiting altered values and transmission of the phenotypic deviations to the subsequent generations led to the successful establishment of mutant lines for the parameters MCV, RBC, and PLT. Analysis of the causative mutation was started in selected lines, thereby revealing a novel mutation in the transferrin receptor gene (Tfrc) in one line. Thus, novel phenotype-driven mouse models were established to analyze the genetic components of hematological disorders.
AU  - Aigner, B.*
AU  - Rathkolb, B.*
AU  - Klempt, M.*
AU  - Wagner, S.
AU  - Michel, D.
AU  - Klaften, M.
AU  - Laufs, J.*
AU  - Schneider, B.*
AU  - Sedlmeier, R.*
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
C1  - 6577
C2  - 28931
SP  - 495-505
TI  - Generation of N-ethyl-N-nitrosourea-induced mouse mutants with deviations in hematological parameters.
JO  - Mamm. Genome
VL  - 22
IS  - 9-10
PB  - Springer
PY  - 2011
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - A new spontaneous mouse mutant was characterized by closed eyelids at weaning and without apparent eyes (provisional gene name, eyeless; provisional gene symbol, eyl). The mutation follows a recessive pattern of inheritance and was mapped to the region of chromosome 19 containing Pitx3. Genetic complementation tests using Pitx3 ( ak/+ ) mice confirmed eyl as a new allele of Pitx3 (Pitx3 ( eyl )). Sequencing of the Pitx3 gene in eyl mutants identified an inserted G after cDNA position 416 (416insG; exon 4). The shifted open reading frame is predicted to result in a hybrid protein still containing the Pitx3 homeobox, but followed by 121 new amino acids. The novel Pitx3 ( eyl/eyl ) mutants expressed ophthalmological and brain defects similar to Pitx3 ( ak/ak ) mice: microphthalmia or anophthalmia and loss of dopamine neurons of the substantia nigra. In addition, we observed in the homozygous eyeless mutants increased extramedullary hematopoiesis in the spleen, frequently liver steatosis, and reduced body weight. There were also several behavioral changes in the homozygous mutants, including reduced forelimb grip strength and increased nociception. In addition to these alterations in both sexes, we observed in female Pitx3 ( eyl/eyl ) mice increased anxiety-related behavior, reduced locomotor activity, reduced object exploration, and increased social contacts; however, we observed decreased anxiety-related behavior and increased arousal in males. Most of these defects identified in the new Pitx3 mutation are observed in Parkinson patients, making the Pitx3 ( eyl ) mutant a valuable new model. It is the first mouse mutant carrying a point mutation within the coding region of Pitx3.
AU  - Rosemann, M.
AU  - Ivashkevich, A.
AU  - Favor, J.
AU  - Dalke, C.
AU  - Hölter, S.M.
AU  - Becker, L.*
AU  - Rácz, I.*
AU  - Bolle, I.
AU  - Klempt, M.*
AU  - Rathkolb, B.*
AU  - Kalaydjiev, S.*
AU  - Adler, T.*
AU  - Aguilar, A.*
AU  - Hans, W.
AU  - Horsch, M.
AU  - Rozman, J.
AU  - Calzada-Wack, J.
AU  - Kunder, S.
AU  - Naton, B.
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Schulz, S.
AU  - Beckers, J.
AU  - Busch, D.H.*
AU  - Burbach, J.P.*
AU  - Smidt, M.P.*
AU  - Quintanilla-Martinez, L.
AU  - Esposito, I.
AU  - Klopstock, T.*
AU  - Klingenspor, M.*
AU  - Ollert, M.*
AU  - Wolf, E.*
AU  - Wurst, W.
AU  - Zimmer, A.*
AU  - Hrabě de Angelis, M.
AU  - Atkinson, M.J.
AU  - Heinzmann, U.
AU  - Graw, J.
C1  - 1394
C2  - 26743
SP  - 13-27
TI  - Microphthalmia, parkinsonism, and enhanced nociception in Pitx3(416insG ) mice.
JO  - Mamm. Genome
VL  - 21
IS  - 1-2
PB  - Springer
PY  - 2010
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Many of inflammatory diseases, including inflammatory arthritis, are multifactorial bases. The Ali18 semidominant mutation induced by N-ethyl-N-nitrosourea in the C3HeB/FeJ (C3H) genome causes spontaneous inflammation of peripheral limbs and elevated immunoglobulin E (IgE) levels in mice. Although the Ali18 locus was mapped to a single locus on chromosome 4, the arthritic phenotype of Ali18/+ mice was completely suppressed in F1 hybrid genetic backgrounds. To determine the chromosomal locations of the modifier loci affecting the severity of arthritis, an autosomal genome scan of 22 affected Ali18/+ F2 mice was conducted using C57BL/6J as a partner strain. Interestingly, regions on chromosomes 1 and 3 in C3H showed significant genetic interactions. Moreover, 174 N2 (backcross to Ali18/Ali18) and 267 F2 animals were used for measurement of arthritis scores and plasma IgE levels, and also for genotyping with 153 genome-wide single nucleotide polymorphism (SNP) markers. In N2 populations, two significant trait loci for arthritis scores on chromosomes 1 and 15 were detected. Although no significant scores were detected in F2 mice besides chromosome 4, a suggestive score was detected on chromosome 3. In addition, a two-dimensional genome scan using F2 identified five suggestive scores of chromosomal combinations, chromosomes 1 x 10, 2 x 6, 3 x 4, 4 x 9, and 6 x 15. No significant trait loci affecting IgE levels were detected in both N2 and F2 populations. Identification of the Ali18 modifier genes by further detailed analyses such as congenic strains and expression profiling may dissect molecular complexity in inflammatory diseases.
AU  - Abe, K.
AU  - Klaften, M.
AU  - Narita, A.*
AU  - Kimura, T.*
AU  - Imai, K.*
AU  - Kimura, M.*
AU  - Rubio-Aliaga, I.
AU  - Wagner, S.
AU  - Jakob, T.*
AU  - Hrabě de Angelis, M.
C1  - 2085
C2  - 26215
SP  - 152-161
TI  - Genome-wide search for genes that modulate inflammatory arthritis caused by Ali18 mutation in mice.
JO  - Mamm. Genome
VL  - 20
IS  - 3
PB  - Springer
PY  - 2009
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - In vitro fertilization (IVF) and zona pellucida laser microdissection-facilitated IVF (Laser-IVF) are presently routine procedures in human assisted reproduction. The safety of these methods at the epigenetic level is not fully understood. Studies on mouse Laser-IVF embryos provide evidence that the use of Laser-IVF leads to reduced birth rate, indicating a potential harm of this technique for the embryo. Hence, the aim of this study was to examine the difference in DNA methylation pattern between IVF- and Laser-IVF-derived mouse zygotes. We examined two experimental groups of C3HeB/FeJ oocytes: (1) zona-intact and (2) laser-microdissected oocytes that were fertilized in vitro with freshly collected spermatozoa. Zygotes were fixed 5, 8, and 12 h after fertilization, and indirect immunofluorescence staining was studied using an anti-5-methylcytidine (5-MeC) antibody. The fluorescence intensities of paternal and maternal pronuclei were evaluated using the computer-assisted analysis of digital images. In addition, we performed a semiquantitative RT-PCR analysis of the presence of transcripts of three developmental marker genes, Oct4, Dab2, and Dnmt3b, in IVF- and Laser-IVF-derived blastocysts. We observed no significant differences in methylation status of the paternal genome and in the transcripts of the developmental marker genes after IVF and Laser-IVF. In conclusion, epigenetic patterns and early embryonic development are not altered by laser-assisted IVF techniques and another explanation must be sought for the poor implantation rates observed in mice.
AU  - Peters, D.D.
AU  - Lepikhov, K.*
AU  - Rodenacker, K.
AU  - Marschall, S.
AU  - Boersma, A.
AU  - Hutzler, P.
AU  - Scherb, H.
AU  - Walter, J.*
AU  - Hrabě de Angelis, M.
C1  - 669
C2  - 26614
CY  - New York
SP  - 664-673
TI  - Effect of IVF and laser zona dissection on DNA methylation pattern of mouse zygotes.
JO  - Mamm. Genome
VL  - 20
IS  - 9-10
PB  - Springer
PY  - 2009
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - The aim of this study was the application of a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice for the identification of dominant mutations involved in the regulation and modulation of alcohol-drinking behavior. The chemical mutagen ENU was utilized in the generation of 131 male ENU-mutant C57BL/6J mice (G0). These ENU-treated mice were paired with wild-type C57BL/6J mice to generate G1 and subsequent generations. In total, 3327 mice were generated. Starting with G1, mice were screened for voluntary oral self-administration of 10% (v/v) alcohol vs. water in a two-bottle paradigm. From these mice, after a total period of 5 weeks of drinking, 43 mutants fulfilled the criteria of an "alcohol phenotype," that is, high or low ethanol intake. They were then selected for breeding and tested in a "confirmation cross" (G2-G4) for inheritance. Although we did not establish stable high or low drinking lines, several results were obtained in the context of alcohol consumption. First, female mice drank more alcohol than their male counterparts. Second, the former demonstrated greater infertility. Third, all animals displayed relatively stable alcohol intake, although significantly different in two different laboratories. Finally, seasonal and monthly variability was observed, with the highest alcohol consumption occurring in spring and the lowest in autumn. In conclusion, it seems difficult to identify dominant mutations involved in the modulation or regulation of voluntary alcohol consumption via a phenotype-driven ENU mutagenesis screen. In accordance with the findings from knockout studies, we suggest that mainly recessive mutations contribute to an alcohol-drinking or alcohol-avoiding phenotype.
AU  - Pawlak, C.R.*
AU  - Sanchis-Segura, C.
AU  - Soewarto, D.
AU  - Wagner, S.
AU  - Hrabě de Angelis, M.
AU  - Spanagel, R.*
C1  - 4033
C2  - 25157
SP  - 77-84
TI  - A phenotype-driven ENU mutagenesis screen for the identification of dominant mutations involved in alcohol consumption.
JO  - Mamm. Genome
VL  - 19
IS  - 2
PB  - Springer
PY  - 2008
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Understanding the functions encoded in the mouse genome will be central to an understanding of the genetic basis of human disease. To achieve this it will be essential to be able to characterize the phenotypic consequences of variation and alterations in individual genes. Data on the phenotypes of mouse strains are currently held in a number of different forms (detailed descriptions of mouse lines, first-line phenotyping data on novel mutations, data on the normal features of inbred lines) at many sites worldwide. For the most efficient use of these data sets, we have initiated a process to develop standards for the description of phenotypes (using ontologies) and file formats for the description of phenotyping protocols and phenotype data sets. This process is ongoing and needs to be supported by the wider mouse genetics and phenotyping communities to succeed. We invite interested parties to contact us as we develop this process further.
AU  - Hancock, J.M.
AU  - Adams, N.C.
AU  - Aidinis, V.
AU  - Blake, A.
AU  - Blake, J.A.
AU  - Bogue, M.
AU  - Brown, S.D.M.
AU  - Chesler, E.
AU  - Davidson, D.
AU  - Duran, C.
AU  - Eppig, J.T.
AU  - Gailus-Durner, V.
AU  - Gates, H.
AU  - Gkoutos, G.V.
AU  - Greenaway, S.
AU  - Hrabě de Angelis, M.
AU  - Kollias, G.
AU  - Leblanc, S.
AU  - Lee, K.
AU  - Lengger, C.
AU  - Maier, H.
AU  - Mallon, A.M.
AU  - Masuya, H.
AU  - Melvin, D.G.
AU  - Müller, W.
AU  - Parkinson, H.
AU  - Proctor, G.
AU  - Reuveni, E.
AU  - Schofield, P.
AU  - Shukla, A.
AU  - Smith, C.
AU  - Toyoda, T.
AU  - Vasseur, L.
AU  - Wakana, S.
AU  - Walling, A.
AU  - White, J.
AU  - Wood, J.
AU  - Zouberakis, M.
C1  - 4279
C2  - 24398
SP  - 157-163
TI  - Integration of mouse phenome data resources.
JO  - Mamm. Genome
VL  - 18
IS  - 3
PB  - Springer
PY  - 2007
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Housing conditions are known to influence laboratory animal behavior. However, it is not known whether housing mice in individually ventilated cages (IVCs) to maintain optimal hygienic conditions alters behavioral baselines established in conventional housing. This issue is important with regard to comparability and reproducibility of data. Therefore, we investigated the impact of IVC housing on emotionality and fear learning in male C3HeB/FeJ (C3H) and C57BL/6J (B6J) mice housed singly either in conventional type II cages with wire bar lids (Conventional), or in IVCs of the same size, but with smooth, untextured lids (IVC classic), thus acoustically attenuated from external stimuli and with limited climbing facilities compared to Conventional. To evaluate the role of climbing, additional mice were kept in IVCs with lids having wire bars (“grid”) added to the inner surface (IVC grid). Spontaneous behavior, sensorimotor behavior, and fear learning were measured. IVC housing reduced activity and enhanced anxiety-related behavior in both strains, whereas grooming latency was reduced in B6J only. IVC housing increased Acoustic Startle Response in C3H but not in B6J mice. The “grid” did not compensate for these IVC housing effects. In contrast, B6J mice in IVC grid performed best in fear potentiated startle while B6J mice in IVC classic performed the worst, suggesting that climbing facilities combined with IVC housing facilitate FPS performance in singly-housed B6J males. Our data show that IVC housing can affect behavioral performance and can modulate behavioral parameters in a general and a strain-specific manner, thus having an impact on mouse functional genomics.
AU  - Kallnik, M.
AU  - Elvert, R.*
AU  - Ehrhardt, N.*
AU  - Kissling, D.
AU  - Mahabir, E.
AU  - Welzl, G.
AU  - Faus-Kessler, T.
AU  - Hrabě de Angelis, M.
AU  - Wurst, W.
AU  - Schmidt, J.
AU  - Hölter, S.M.
C1  - 1519
C2  - 24396
SP  - 173-186
TI  - Impact of IVC housing on emotionality and fear learning in male C3HeB/FeJ and C57BL/6J mice.
JO  - Mamm. Genome
VL  - 18
IS  - 3
PB  - Springer
PY  - 2007
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - The first mutations causing hereditary glyceraldehyde-3-phosphate dehydrogenase (GAPDH) deficiency in the mouse are described. In the course of various mutagenicity experiments with chemical mutagens and irradiation, nine independent mutations causing approximately 50-55% residual activity in blood compared to wild type were identified at the Gapdh structural locus on chromosome 6. Breeding experiments displayed an autosomal semidominant mode of inheritance for all mutants. Two mutations are homozygous viable producing a GAPDH residual activity of less than 10%. Mortality of the remaining seven homozygous lethal lines occurs at an early postimplantation stage of development. The physiologic and hematologic analyses provided no indication for further altered traits in heterozygotes or homozygotes. The molecular characterization showed base substitutions resulting in amino acid exchanges in seven mutations, in one mutation a transversion creating a stop codon caused a truncated protein of 89 amino acids and two deletions generating truncated proteins of 73 and 9 amino acids, respectively.
AU  - Pretsch, W.
AU  - Favor, J.
C1  - 1794
C2  - 24783
SP  - 686-692
TI  - Genetic, biochemical, and molecular characterization of nine glyceraldehyde-3-phosphate dehydrogenase mutants with reduced enzyme activity in Mus musculus.
JO  - Mamm. Genome
VL  - 18
IS  - 10
PB  - Springer
PY  - 2007
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Inflammation is a complex cellular and humoral response against trauma and infection, and its presence leads to destruction of tissue in humans. The mechanisms that initiate inflammatory diseases remain largely unknown because of complex interactions between multiple genetic and environmental factors during pathogenesis. Animal models for human diseases offer dissection of complex pathogenesis by inbred genetic backgrounds and controlled circumstances. In this article we report a chemically induced new mutation, Ali18 (Abnormal limb), as a mouse model for inflammatory arthritis and dermatitis. Ali18/+ mice exhibit rubor and swelling of footpads in hindlimbs in adults. In Ali18/Ali18 mice, the digits in forelimbs and hindlimbs and tails were necrotic and/or deformed by severe swelling. Histologic analysis revealed infiltration of mixed populations of inflammatory cells into bone marrow, peripheral joints, and skin in the affected areas of Ali18/Ali18 mice. In addition, generalized osteoporosis-like phenotypes were confirmed by dual energy X-ray absorptiometry (DXA), microcomputed tomography (μCT), and peripheral quantitative computed tomography (pQCT) in homozygous animals. Whereas the Ali18 mutation was mapped to a single locus, the phenotype presentation was altered by complex modifier effects from other inbred genetic backgrounds. Detailed analysis of the Ali18 phenotype and identification of the mutation and its modifier genes may provide molecular insights into the complex nature of inflammatory diseases and the relationship between inflammation and bone metabolism. © Springer Science+Business Media, Inc. 2006.
AU  - Abe, K.*
AU  - Fuchs, H.
AU  - Lisse, T.S.
AU  - Hans, W.
AU  - Hrabě de Angelis, M.
C1  - 5691
C2  - 23828
SP  - 915-926
TI  - New ENU-induced semidominant mutation, Ali18, causes inflammatory arthritis, dermatitis and osteoporosis in the mouse.
JO  - Mamm. Genome
VL  - 17
IS  - 9
PY  - 2006
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Mice are important models for biomedical research because of the possibility of standardizing genetic background and environmental conditions, which both affect phenotypic variability. Inbred mouse strains as well as F1 hybrid mice are routinely used as genetically defined animal models; however, only a few studies investigated the variance of phenotypic parameters in inbred versus F1 hybrid mice and the potential interference of the genetic background with different housing conditions. Thus, we analyzed the ranges of clinical chemical and hematologic parameters in C3H and C57BL/6 inbred mice and their reciprocal F1 hybrids (B6C3F1, C3B6F1) in two different mouse facilities. Two thirds of the blood parameters examined in the same strain differed between the facilities for both the inbred strains and the F1 hybrid lines. The relation of the values between inbred and F1 hybrid mice was also affected by the facility. The variance of blood parameters in F1 hybrid mice compared with their parental inbred strains was inconsistent in one facility but generally smaller in the other facility. A subsequent study of F1 hybrid animals derived from the parental strains C3H and BALB/c, which was done in the latter housing unit, detected no general difference in the variance of blood parameters between F1 hybrid and inbred mice. Our study clearly demonstrates the possibility of major interactions between genotype and environment regarding the variance of clinical chemical and hematologic parameters.
AU  - Klempt, M.*
AU  - Rathkolb, B.*
AU  - Fuchs, E.*
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
AU  - Aigner, B.*
C1  - 3552
C2  - 23449
SP  - 93-102
TI  - Genotype-specific environmental impact on the variance of blood values in inbred and F1 hybrid mice.
JO  - Mamm. Genome
VL  - 17
PY  - 2006
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - In the mouse, only a few genes have been definitively associated with a small-eye phenotype; the paired-box gene Pax6 and the gene coding for the microphthalmia-associated transcription factor (Mitf). Mutant alleles were recovered by crude phenotype screens and their effects on eye size are relatively large. This feature points to a bias during screening for eye-size mutants, selecting preferentially more severe phenotypes. An unbiased method determining eye-size parameters in an observer-independent, quantitative manner is expected to pick up variations in other genes, which will be confirmed as pathologic mutations in confirmation crosses. The present study used optical low coherent interferometry (OLCI) to compare the axial eye length, the cornea and lens thicknesses, and the anterior chamber depth in four common wild-type, laboratory inbred strains (C57BL/6J, C3HeB/FeJ, 129S2/SvPasCrl, and BALB/cByJ) between 4 and 15 weeks of age. There were no differences between left and right eyes; differences between the size parameters of males and females have been observed only in a few cases. An optimal screening age for OLCI measurements was defined as 11 weeks of age. At this age, we checked two other inbred strains (AKR/J and DBA/2NCrl) as well as CD-1 outbred mice. CD-1 mice have the largest axial length. The most impressive differences among inbred strains were, first, the anterior chamber depth, where the DBA mice have significantly lower values than the other strains. Second, the cornea in C3H mice is approximately 20% thicker than in the other inbred strains. Finally, wild-type intervals (mean ± 3 SD) for axial length, anterior chamber depth, and cornea and lens thicknesses were calculated allowing a quick identification of pathologic outliers.
AU  - Puk, O.
AU  - Dalke, C.
AU  - Favor, J.
AU  - Hrabě de Angelis, M.
AU  - Graw, J.
C1  - 2538
C2  - 23855
SP  - 851-857
TI  - Variations of eye size parameters among different strains of mice.
JO  - Mamm. Genome
VL  - 17
PY  - 2006
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - We have analyzed two novel mouse mutant strains, Rco12 and Rco13, displaying a wavy pelage and curly vibrissae that have been identified in an ENU screen for dominant mutations affecting the pelage. The mutations were mapped to mouse Chromosome 15 and identified as missense point mutations in the first exon of the Krt71 (formerly called Krt2-6g) gene causing alterations of amino acid residue 143 from alanine to glycine (Rco12) and residue 146 from isoleucine to phenylalanine. The morphologic analyses demonstrated that both mutations cause identical phenotypes leading to the formation of filamentous aggregates in Henle’s and Huxley’s layers of the inner root sheath (IRS) of the hair follicle that leads to the bending of the hair shaft. Both novel mutations are located in the immediate vicinity of previously identified mutations in murine Krt71 that cause similar phenotypes and alter the helix initiation motif of the keratin. The characterization of these mutants demonstrates the importance of this Krt71 domain for the formation of linear IRS intermediate filaments
AU  - Runkel, F.*
AU  - Klaften, M.*
AU  - Koch, K.*
AU  - Böhnert, V.*
AU  - Büssow, H.*
AU  - Fuchs, H.
AU  - Franz, T.*
AU  - Hrabě de Angelis, M.
C1  - 5113
C2  - 24156
SP  - 1172-1182
TI  - Morphologic and molecular characterization of two novel Krt71 (Krt2-6g) mutations : Krt71(rco12) and Krt71(rco13).
JO  - Mamm. Genome
VL  - 17
PY  - 2006
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Comparative genomewide expression profiling is a powerful tool in the effort to annotate the mouse genome with biological function. The systematic analysis of RNA expression data of mouse lines from the Munich ENU mutagenesis screen might support the understanding of the molecular biology of such mutants and provide new insights into mammalian gene function. In a direct comparison of DNA microarray experiments of individual versus pooled RNA samples of organs from ENU-induced mouse mutants, we provide evidence that individual RNA samples may outperform pools in some aspects. Genes with high biological variability in their expression levels (noisy genes) are identified as false positives in pooled samples. Evidence suggests that highly stringent housing conditions and standardized procedures for the isolation of organs significantly reduce biological variability in gene expression profiling experiments. Data on wild-type individuals demonstrate the positive effect of controlling variables such as social status, food intake before organ sampling, and stress with regard to reproducibility of gene expression patterns. Analyses of several organs from various ENU-induced mutant lines in general show low numbers of differentially expressed genes. We demonstrate the feasibility to detect transcriptionally affected organs employing RNA expression profiling as a tool for molecular phenotyping.
AU  - Seltmann, M.
AU  - Horsch, M.
AU  - Drobyshev, A.L.
AU  - Chen, Y.*
AU  - Hrabě de Angelis, M.
AU  - Beckers, J.
C1  - 1586
C2  - 22478
SP  - 1-10
TI  - Assessment of a systematic expression profiling approach in ENU-induced mouse mutant lines.
JO  - Mamm. Genome
VL  - 16
PY  - 2005
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Tcm (total cataract with microphthalmia) is an autosomal dominant mouse eye mutation. Heterozygous Tcm/+ mice are born with several eye malformations including microphthalmia, retinal and iris dysplasia, total lens cataract, and ventral coloboma. The Tcm mutation was previously mapped to a 26-Mb region on Chr 4 between D4Mit235 and D4Mit106. In this study, we characterize the Tcm/Tcm homozygous mutant and find they are viable but severely microphthalmic. The developing eye in the Tcm/Tcm homozygote shows defects during early eye development, before formation of the optic cup. Further genetic mapping reduced the Tcm critical region to a 1.3-Mb region bordered by SNPs rs3666764 and rs3713818. This critical region contains two known genes (Asph and Gfd6) and three predicted genes, all of which are positional candidates for Tcm. Sequence analysis of Tcm genomic DNA revealed no mutations in the coding regions and splice site junctions of the five candidate genes. These results indicate that the causitive Tcm mutation falls within a noncoding regulatory region of one of the five candidate genes or in an undescribed gene.
AU  - Wang, K.S.*
AU  - Zahn, L.E.*
AU  - Favor, J.
AU  - Huang, K.M.*
AU  - Stambolian, D.*
C1  - 4800
C2  - 23066
SP  - 332-343
TI  - Genetic and phenotypic analysis of Tcm, a mutation affecting early eye development.
JO  - Mamm. Genome
VL  - 16
PY  - 2005
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Ahituv, N.*
AU  - Erven, A.*
AU  - Fuchs, H.
AU  - Guy, K.*
AU  - Ashery-Padan, R.*
AU  - Williams, T.*
AU  - Hrabě de Angelis, M.
AU  - Avraham, K.B.*
AU  - Steel, K.P.*
C1  - 3885
C2  - 21968
SP  - 424-432
TI  - An ENU-induced mutation in AP-2alpha leads to middle ear and ocular defects in Doarad mice.
JO  - Mamm. Genome
VL  - 15
PY  - 2004
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - X-linked hypophosphatemic rickets (XLH) in humans is caused by mutations in the PHEX gene. Previously, three mutations in the mouse Phex gene have been reported: Phex  Hyp , Gy, and Phex  Ska1 . Here we report analysis of two new spontaneous mutations in the mouse Phex gene, Phex  Hyp-2J  and Phex  Hyp-Duk . Phex  Hyp-2J  and Phex  Hyp-Duk  involve intragenic deletions of at least 7.3 kb containing exon 15, and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition, mice carrying the Phex  Hyp-Duk  mutation exhibit background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology, demonstrating the influence of modifying genes on Phex-related phenotypes. Cochlear cross-sections from Phex  Hyp-2J /Y and Phex  Hyp-Duk /Y males reveal a thickening of the temporal bone surrounding the cochlea with the presence of a precipitate in the scala tympani. Evidence of the degeneration of the organ of Corti and spiral ganglion also are present in the hearing-impaired Phex  Hyp-Duk /Y mice, but not in the normal-hearing Phex  Hyp-2J/Y mice. Analysis of the phenotypes noted in Phex  Hyp-Duk /Y an Phex  Hyp-2J /Y males, together with those noted in Phex  Ska1 /Y and Phex  Hyp /Y males, now allow XLH-related phenotypes to be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males. Also, identification of the genetic modifiers of hearing and craniofacial dysmorphology in Phex  Hyp-Duk /Y mice could provide insight into the phenotypic variation of XLH in humans.
AU  - Lorenz-Depiereux, B.
AU  - Guido, V.E.*
AU  - Johnson, K.R.*
AU  - Zheng, Q.Y.*
AU  - Gagnon, L.H.*
AU  - Bauschatz, J.D.*
AU  - Davisson, M.T.*
AU  - Washburn, L.L.*
AU  - Donahue, L.R.*
AU  - Strom, T.M.
AU  - Eicher, E.M.*
C1  - 2322
C2  - 21818
SP  - 151-161
TI  - New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.
JO  - Mamm. Genome
VL  - 15
PY  - 2004
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Multiple endocrine neoplasia-like syndrome (MENX) is a hereditary cancer syndrome in the rat characterized by inborn cataract and multiple tumors affecting the neuroendocrine system developed within the first year of life. The spectrum of affected organs is intermediate between MEN type 1 (MEN1) and MEN type 2 (MEN2) syndromes in human, but, in contrast to them, MENX is inherited in a recessive fashion. Here we report the mapping of the MENX locus to rat Chromosome (Chr) 4 by a genome-wide linkage analysis. This analysis was done in 41 animals obtained from a (Wistar/Nhg x SDwe) x SDwe interstrain backcross, where SDwe (Sprague-Dawley white eye) indicates the affected animals. The MENX disease locus was ultimately mapped to a similar to22-cM interval on Chr 4 that includes the rat homolog of the human RET proto-oncogene. As activating point mutations of RET are known to be responsible for MEN2 in human, we analyzed several markers located in the proximity of Ret for linkage to the disease phenotype. Our data exclude Ret involvement in MENX and establish that a second gene, playing a role in endocrine tumor formation, lies within the distal. part of rat Chr 4. Although heritable human endocrine tumors are quite rare, sporadic tumors of MEN-affected tissues occur at a much higher frequency, and their pathogenesis is poorly understood. The identification of the MENX gene should contribute to our understanding of the genetic mechanisms of neuroendocrine tissue tumorigenesis and may assist in developing new and more appropriate therapeutic strategies for these diseases.
AU  - Piotrowska, K.
AU  - Pellegata, N.S.
AU  - Rosemann, M.
AU  - Fritz, A.
AU  - Graw, J.
AU  - Atkinson, M.J.
C1  - 4052
C2  - 21726
SP  - 135-141
TI  - Mapping of a novel MEN-like syndrome locus to rat Chromosome 4.
JO  - Mamm. Genome
VL  - 15
IS  - 2
PY  - 2004
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - A phenotype-driven approach was adopted in the mouse to identify molecules involved in ear development and function. Mutant mice were obtained using N-ethyl-N-nitrosourea (ENU) mutagenesis and were screened for dominant mutations that affect hearing and/or balance. Heterozygote headbanger (Hdb/+) mutants display classic behavior indicative of vestibular dysfunction including hyperactivity and head bobbing, and they show a Preyer reflex in response to sound but have raised cochlear thresholds especially at low frequencies. Scanning electron microscopy of the surface of the organ of Corti revealed abnormal stereocilia bundle development from an early age that was more severe in the apex than the base. Utricular stereocilia were long, thin, and wispy. Homozygotes showed a similar but more severe phenotype. The headbanger mutation has been mapped to a 1.5-cM region on mouse Chromosome 7 in the region of the unconventional myosin gene Myo7a, and mutation screening revealed an A>T transversion that is predicted to cause an isoleucine-to-phenylalanine amino acid substitution (I178F) in a conserved region in the motor-encoding domain of the gene. Protein analysis revealed reduced levels of myosin VIIa expression in inner ears of headbanger mice. Headbanger represents a novel inner ear phenotype and provides a potential model for low-frequency-type human hearing loss.
AU  - Rhodes, C.R.*
AU  - Hertzano, R.*
AU  - Fuchs, H.
AU  - Bell, R.E.*
AU  - Hrabě de Angelis, M.
AU  - Steel, K.P.*
AU  - Avraham, K.B.*
C1  - 1758
C2  - 22147
SP  - 686-697
TI  - A Myo7a mutation cosegregates with stereocilia defects and low-frequency hearing impairment.
JO  - Mamm. Genome
VL  - 15
PY  - 2004
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - During a large-scale ENU mutagenesis screen, a mouse mutant with a dominant cataract was detected and referred to as Aey4. Aim of this studs was the morphological description of the mutant. the mapping of the mutation. and the characterization of the underlying molecular lesion. The slit-lamp examination revealed a strong nuclear cataract surrounded by a homogeneous milky opacity in the inner cortex. The histological analysis demonstrated remnants of cell nuclei throughout the entire lens. The mutation was mapped to Chromosome 1 by a genome-wide linkage making the six gamma-crystallin encoding genes and the closely linked betaA2-crystallin encoding gene to relevant candidate genes. Finally, a T-->A exchange in exon 2 of the gammaD-crystallin encoding gene (symbol: Crygd) was demonstrated to be causative for the cataract phenotype: this particular mutation is. therefore, referred to Crygo(Aey4) . The alteration in codon 76 leads to an amino acid exchange of Val-->Asp. Val at this position is highly conserved: it is found in all mouse and rat gammaD/E/F-crystallins as well as in the human gammaA- and gammaD-crystallins. It may, be replaced solely by Ile. which is present in all bovine gamma-crystallins, in the rat and mouse gammaA/B/C-crystallins, as well as in the human gammaB/C-crystallins. It is predicted that the exchange of a hydrophobic side chain by a polar and acidic one might influence the microenvironment by a dramatic decrease of the isoelectric point by 1.5 pH units in the 10 amino acids surrounding position 76. The Crygd(Aey4) additionally demonstrates the importance of the integrity of the Cryg gene cluster for lens transparency.
AU  - Graw, J.
AU  - Löster, J.
AU  - Soewarto, D.
AU  - Fuchs, H.
AU  - Reis, A.*
AU  - Wolf, E.*
AU  - Balling, R.
AU  - Hrabě de Angelis, M.
C1  - 10007
C2  - 20416
SP  - 452-455
TI  - V76D mutation in a conserved gammaD-crystallin region leads to dominant cataracts in mice.
JO  - Mamm. Genome
VL  - 13
PB  - Springer
PY  - 2002
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Reinhard, C.
AU  - Eder, G.
AU  - Fuchs, H.
AU  - Ziesenis, A.
AU  - Heyder, J.
AU  - Schulz, S.
C1  - 10008
C2  - 20728
SP  - 429-437
TI  - Inbred strain variation in lung function.
JO  - Mamm. Genome
VL  - 13
PY  - 2002
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Gene expression is presently a major focus in genome analysis, and the experimental data on regulatory mechanisms and functional transcription factor binding sites are steadily growing. However, the annotation of transcriptional regulation of sequences cannot keep pace with the exponential growth of sequence databases. Employing detailed experimental data of a single promoter or enhancer to predict genes with similar regulation would provide a powerful method to link the literature about transcriptional regulation and sequence databases. To this end, we used information on individual functional transcription factor binding sites to compose in silico promoter and enhancer models of muscle-specific genes and to analyze the rodents section of EMBL with these models. Exhaustive evaluation of all hits revealed every second to third match to be a muscle-associated gene. Moreover, functionally related regulatory regions were detected by our model-based approach even in the absence of sequence similarity. We believe that this new approach is a substanial extension to database analysis by BLAST or FASTA, which are restricted to sequence similarity.
AU  - Gailus-Durner, V.
AU  - Scherf, M.
AU  - Werner, T.
C1  - 10005
C2  - 22358
SP  - 67-72
TI  - Experimental data of a single promoter can be used for in silico detection of genes with related regulation in the absence of sequence similarity.
JO  - Mamm. Genome
VL  - 12
PY  - 2001
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - As a first step towards the identification of cis-regulatory elements of Pax9 by means of comparative genomics, we have analyzed genome regions encompassing the Pax9 gene in three vertebrate species, humans, mice (Mus musculus), and the Japanese pufferfish (Fugu rubripes). We show the genomic organization of Pax9 and its physical association with Nkx2-9 conserved in the three species. We discuss about possible implications of the conserved synteny between Pax9 and Nkx2-9 in a context of vertebrate evolution. This report also includes the first description of the primary structures of Fugu Pax9 and Nkx2-9. Furthermore, we report the identification of a novel upstream exon and putative transcription start sites in mouse Pax9. Our results suggest that transcription of Pax9 may be initiated at two alternative start sites and driven by TATA-less promoters.
AU  - Santagati, F.
AU  - Gerber, J.-K.
AU  - Blusch, J.H.
AU  - Kokubu, C.
AU  - Peters, H.
AU  - Adamski, J.
AU  - Werner, T.
AU  - Balling, R.
AU  - Imai, K.
C1  - 10006
C2  - 22336
SP  - 232-237
TI  - Comparative analysis of the genomic organization of Pax9 and its conserved physical association with Nkx2-9 in the human, mouse and pufferfish genomes.
JO  - Mamm. Genome
VL  - 12
PY  - 2001
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Balling, R.*
AU  - Brown, S.*
AU  - Hrabě de Angelis, M.
AU  - Justice, M.*
AU  - Nadeau, J.*
AU  - Peters, J.*
C1  - 22709
C2  - 31132
SP  - 471-471
TI  - Great times for mouse genetics: Getting ready for large-scale ENU-mutagenesis.
JO  - Mamm. Genome
VL  - 11
IS  - 7
PB  - Springer
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - The immunology screen focuses on the identification of novel gene products involved in the mammalian immune response and on the establishment of mouse models for immunological disorders. For this purpose, high throughput and semi-automated techniques were developed and optimized for low cost per sample and reproducibility. All assays are designed to be nonconsumptive and are based on peripheral blood or direct PCR amplification.
AU  - Flaswinkel, H.*
AU  - Alessandrini, F.
AU  - Rathkolb, B.*
AU  - Decker, T.-M.*
AU  - Kremmer, E.
AU  - Servatius, A.*
AU  - Jakob, T.
AU  - Soewarto, D.
AU  - Marschall, S.
AU  - Fella, C.
AU  - Behrendt, H.
AU  - Ring, J.
AU  - Wolf, E.*
AU  - Balling, R.
AU  - Hrabě de Angelis, M.
AU  - Pfeffer, K.*
C1  - 22713
C2  - 31134
SP  - 526-527
TI  - Identification of immunological relevant phenotypes in ENU mutagenized mice.
JO  - Mamm. Genome
VL  - 11
IS  - 7
PB  - Springer
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Fuchs, H.
AU  - Schughart, K.*
AU  - Wolf, E.*
AU  - Balling, R.
AU  - Hrabě de Angelis, M.
C1  - 22306
C2  - 21112
SP  - 528-530
TI  - Screening for dysmorphological abnormalities-a powerful tool to isolate new mouse mutants.
JO  - Mamm. Genome
VL  - 11
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - The germline supermutagen, N-ethyl-N-nitrosourea (ENU), has a variety of effects on mice. ENU is a toxin and carcinogen as well as a mutagen, and strains differ in their susceptibility to its effects. Therefore, it is necessary to determine an appropriate mutagenic, non-toxic dose of ENU for strains that are to be used in experiments. In order to provide some guidance, we have compiled data from a number of laboratories that have exposed male mice from inbred and non-inbred strains or their F(1) hybrids to ENU. The results show that most F(1) hybrid animals tolerate ENU well, but that inbred strains of mice vary in their longevity and in their ability to recover fertility after treatment with ENU.
AU  - Justice, M.J.*
AU  - Carpenter, D.A.*
AU  - Favor, J.
AU  - Neuhäuser-Klaus, A.
AU  - Hrabě de Angelis, M.
AU  - Soewarto, D.
AU  - Moser, A.*
AU  - Cordes, S.*
AU  - Miller, D.*
AU  - Chapman, V.*
AU  - Weber, J.S.*
AU  - Rinchik, E.M.*
AU  - Hunsicker, P.R.*
AU  - Russell, W.L.*
AU  - Bode, V.C.*
C1  - 22721
C2  - 31137
SP  - 484-488
TI  - Effects of ENU dosage on mouse strains.
JO  - Mamm. Genome
VL  - 11
IS  - 7
PB  - Springer
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Knapik, E.W.
C1  - 21405
C2  - 19521
SP  - 511-519
TI  - ENU mutagenesis in zebrafish-from genes to complex diseases.
JO  - Mamm. Genome
VL  - 11
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Pargent, W.
AU  - Heffner, S.
AU  - Schäble, K.-H.
AU  - Soewarto, D.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
C1  - 22311
C2  - 21118
SP  - 590-593
TI  - MouseNet databases : Digital management of a large-scale mutagenesis project.
JO  - Mamm. Genome
VL  - 11
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Rathkolb, B.*
AU  - Decker, T.-M.*
AU  - Fuchs, E.*
AU  - Soewarto, D.
AU  - Fella, C.
AU  - Heffner, S.
AU  - Pargent, W.
AU  - Wanke, R.*
AU  - Balling, R.
AU  - Hrabě de Angelis, M.
AU  - Kolb, H.-J.*
AU  - Wolf, E.*
C1  - 10009
C2  - 21114
SP  - 543-546
TI  - The clinical-chemical screen in the Munich ENU Mouse Mutagenesis Project : Screening for clinically relevant phenotypes.
JO  - Mamm. Genome
VL  - 11
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Rolinski, B.*
AU  - Arnecke, R.*
AU  - Dame, T.*
AU  - Kreischer, J.*
AU  - Olgemöller, B.*
AU  - Wolf, E.*
AU  - Balling, R.
AU  - Hrabě de Angelis, M.
AU  - Roscher, A.A.*
C1  - 22308
C2  - 21115
SP  - 547-551
TI  - The biochemical metabolite screen in the Munich ENU Mouse Mutagenesis Project : Determination of amino acids and acylcarnitines by tandem mass spectrometry.
JO  - Mamm. Genome
VL  - 11
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AB  - Recent in vivo and in vitro data of patients analyzed for genetic susceptibility to radiation during cancer therapy have shown structural changes in the chromosomes to be prevalent both in the patients being treated and in their immediate family members. As structural changes in chromosomes frequently lead to activation of proto-oncogenes and elimination of tumor-suppressor genes, they represent important mechanisms for the initiation of DNA repair processes and tumorigenesis. With the exception of rare genetic syndromes such as AT (Ataxia telangiectasia) or NBS (Nijmegen Breakage Syndrome), the background for the inheritance of genetic susceptibility to radiation is unknown.
      
      	Recently, a large-scale genetic screen of mouse mutants has been established within the German Human Genome Project (Hrabè de Angelis and Balling 1998). The goal of this ENU (ENU: ethylnitrosourea) mutagenesis screen is the generation of mutant mice that will serve as animal models for human diseases and genetic susceptibility.
      
      	In order to fully utilize the potential of a genetic screen of this magnitude, in which exploration for genes responsible for genomic instability and radiation sensitivity is to occur, it is necessary to establish a simple assay system that is amenable to automation. Hence, we are using the single-cell gel electrophoresis (comet assay) to detect mouse mutants that display a genetic susceptibility to ionizing radiation. We have established the analysis parameters in the comet assay which are currently used to detect radiation-sensitive mouse mutants and to control the variance within the mouse population in the ENU screen. The assay can be used to isolate genes that are responsible for DNA repair and radiation sensitivity in mouse and human
AU  - Schindewolf, C.
AU  - Lobenwein, K.
AU  - Trinczek, K.*
AU  - Gomolka, M.*
AU  - Soewarto, D.
AU  - Fella, C.
AU  - Pargent, W.
AU  - Singh, N.*
AU  - Jung, T.*
AU  - Hrabě de Angelis, M.
C1  - 22309
C2  - 21116
SP  - 552-554
TI  - Comet assay as a tool to screen for mouse models with inherited radiation sensitivity.
JO  - Mamm. Genome
VL  - 11
PY  - 2000
SN  - 0938-8990
ER  - 

TY  - JOUR
AU  - Soewarto, D.
AU  - Fella, C.
AU  - Teubner, A.
AU  - Rathkolb, B.*
AU  - Pargent, W.
AU  - Heffner, S.
AU  - Marschall, S.
AU  - Wolf, E.*
AU  - Balling, R.
AU  - Hrabě de Angelis, M.
C1  - 22310
C2  - 21117
SP  - 507-510
TI  - The large-scale Munich ENU-mouse-mutagenesis screen.
JO  - Mamm. Genome
VL  - 11
PY  - 2000
SN  - 0938-8990
ER  -