TY  - JOUR
AB  - Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.
AU  - Hammann, N.*
AU  - Lenz, D.*
AU  - Baric, I.*
AU  - Crushell, E.*
AU  - Vici, C.D.*
AU  - Distelmaier, F.*
AU  - Feillet, F.*
AU  - Freisinger, P.*
AU  - Hempel, M.*
AU  - Khoreva, A.L.*
AU  - Laass, M.W.*
AU  - Lacassie, Y.*
AU  - Lainka, E.*
AU  - Larson-Nath, C.*
AU  - Li, Z.*
AU  - Lipiński, P.*
AU  - Lurz, E.*
AU  - Megarbane, A.*
AU  - Nobre, S.*
AU  - Olivieri, G.*
AU  - Peters, B.*
AU  - Prontera, P.*
AU  - Schlieben, L.D.
AU  - Seroogy, C.M.*
AU  - Sobacchi, C.*
AU  - Suzuki, S.C.*
AU  - Tran, C.L.*
AU  - Vockley, J.*
AU  - Wang, J.S.*
AU  - Wagner, M.
AU  - Prokisch, H.
AU  - Garbade, S.F.*
AU  - Kolker, S.*
AU  - Hoffmann, G.F.*
AU  - Staufner, C.*
C1  - 69817
C2  - 55264
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.
JO  - Mol. Genet. Metab.
VL  - 141
IS  - 3
PB  - Academic Press Inc Elsevier Science
PY  - 2024
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - The diagnosis of Mendelian disorders has notably advanced with integration of whole exome and genome sequencing (WES and WGS) in clinical practice. However, challenges in variant interpretation and uncovered variants by WES still leave a substantial percentage of patients undiagnosed. In this context, integrating RNA sequencing (RNA-seq) improves diagnostic workflows, particularly for WES inconclusive cases. Additionally, functional studies are often necessary to elucidate the impact of prioritized variants on gene expression and protein function. Our study focused on three unrelated male patients (P1-P3) with ATP6AP1-CDG (congenital disorder of glycosylation), presenting with intellectual disability and varying degrees of hepatopathy, glycosylation defects, and an initially inconclusive diagnosis through WES. Subsequent RNA-seq was pivotal in identifying the underlying genetic causes in P1 and P2, detecting ATP6AP1 underexpression and aberrant splicing. Molecular studies in fibroblasts confirmed these findings and identified the rare intronic variants c.289-233C > T and c.289-289G > A in P1 and P2, respectively. Trio-WGS also revealed the variant c.289-289G > A in P3, which was a de novo change in both patients. Functional assays expressing the mutant alleles in HAP1 cells demonstrated the pathogenic impact of these variants by reproducing the splicing alterations observed in patients. Our study underscores the role of RNA-seq and WGS in enhancing diagnostic rates for genetic diseases such as CDG, providing new insights into ATP6AP1-CDG molecular bases by identifying the first two deep intronic variants in this X-linked gene. Additionally, our study highlights the need to integrate RNA-seq and WGS, followed by functional validation, in routine diagnostics for a comprehensive evaluation of patients with an unidentified molecular etiology.
AU  - Morales-Romero, B.*
AU  - Muñoz-Pujol, G.*
AU  - Artuch, R.*
AU  - García-Cazorla, A.*
AU  - O'Callaghan, M.*
AU  - Sykut-Cegielska, J.*
AU  - Campistol, J.M.*
AU  - Moreno-Lozano, P.J.*
AU  - Oud, M.M.*
AU  - Wevers, R.A.*
AU  - Lefeber, D.J.*
AU  - Esteve-Codina, A.*
AU  - Yépez, V.A.*
AU  - Gagneur, J.*
AU  - Wortmann, S.B.*
AU  - Prokisch, H.
AU  - Ribes, A.*
AU  - García-Villoria, J.*
AU  - Tort, F.*
C1  - 70846
C2  - 55951
TI  - Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing.
JO  - Mol. Genet. Metab.
VL  - 142
IS  - 3
PY  - 2024
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Recessive variants in NDUFAF3 are a known cause of complex I (CI)-related mitochondrial disorders (MDs). The seven patients reported to date exhibited severe neurologic symptoms and lactic acidosis, followed by a fatal course and death during infancy in most cases. We present a 10-year-old patient with a neurodevelopmental disorder, progressive exercise intolerance, dystonia, basal ganglia abnormalities, and elevated lactate concentration in blood. Trio-exome sequencing revealed compound-heterozygosity for a pathogenic splice-site and a likely pathogenic missense variant in NDUFAF3. Spectrophotometric analysis of fibroblast-derived mitochondria demonstrated a relatively mild reduction of CI activity. Complexome analyses revealed severely reduced NDUFAF3 as well as CI in patient fibroblasts. Accumulation of early sub-assemblies of the membrane arm of CI associated with mitochondrial complex I intermediate assembly (MCIA) complex was observed. The most striking additional findings were both the unusual occurrence of free monomeric CI holding MCIA and other assembly factors. Here we discuss our patient in context of genotype, phenotype and metabolite data from previously reported NDUFAF3 cases. With the atypical presentation of our patient, we provide further insight into the phenotypic spectrum of NDUFAF3-related MDs. Complexome analysis in our patient confirms the previously defined role of NDUFAF3 within CI biogenesis, yet adds new aspects regarding the correct timing of both the association of soluble and membrane arm modules and CI-maturation as well as respiratory supercomplex formation.
AU  - van der Ven, A.T.*
AU  - Cabrera-Orefice, A.*
AU  - Wente, I.*
AU  - Feichtinger, R.G.*
AU  - Tsiakas, K.*
AU  - Weiss, D.*
AU  - Bierhals, T.*
AU  - Scholle, L.*
AU  - Prokisch, H.
AU  - Kopajtich, R.
AU  - Santer, R.*
AU  - Mayr, J.A.*
AU  - Hempel, M.*
AU  - Wittig, I.*
C1  - 68003
C2  - 54481
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Expanding the phenotypic and biochemical spectrum of NDUFAF3-related mitochondrial disease.
JO  - Mol. Genet. Metab.
VL  - 140
IS  - 3
PB  - Academic Press Inc Elsevier Science
PY  - 2023
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Cardiac dysfunction is a common phenotypic manifestation of primary mitochondrial disease with multiple nuclear and mitochondrial DNA pathogenic variants as a cause, including disorders of mitochondrial translation. To date, five patients have been described with pathogenic variants in MRPL44, encoding the ml44 protein which is part of the large subunit of the mitochondrial ribosome (mitoribosome). Three presented as infants with hypertrophic cardiomyopathy, mild lactic acidosis, and easy fatigue and muscle weakness, whereas two presented in adolescence with myopathy and neurological symptoms. We describe two infants who presented with cardiomyopathy from the neonatal period, failure to thrive, hypoglycemia and in one infant lactic acidosis. A decompensation of the cardiac function in the first year resulted in demise. Exome sequencing identified compound heterozygous variants in the MRPL44 gene including the known pathogenic variant c.467 T > G and two novel pathogenic variants. We document a combined respiratory chain enzyme deficiency with emphasis on complex I and IV, affecting heart muscle tissue more than skeletal muscle or fibroblasts. We show this to be caused by reduced mitochondrial DNA encoded protein synthesis affecting all subunits, and resulting in dysfunction of complex I and IV assembly. The degree of oxidative phosphorylation dysfunction correlated with the impairment of mitochondrial protein synthesis due to different pathogenic variants. These functional studies allow for improved understanding of the pathogenesis of MRPL44-associated mitochondrial disorder.
AU  - Friederich, M.W.*
AU  - Geddes, G.C.*
AU  - Wortmann, S.B.*
AU  - Punnoose, A.*
AU  - Wartchow, E.*
AU  - Knight, K.M.*
AU  - Prokisch, H.
AU  - Creadon-Swindell, G.*
AU  - Mayr, J.A.*
AU  - van Hove, J.L.K.*
C1  - 62305
C2  - 50601
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 362-371
TI  - Pathogenic variants in MRPL44 cause infantile cardiomyopathy due to a mitochondrial translation defect.
JO  - Mol. Genet. Metab.
VL  - 133
IS  - 4
PB  - Academic Press Inc Elsevier Science
PY  - 2021
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0–6 months of age). Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs). All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age. The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs. In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.
AU  - Conte, F.*
AU  - Morava, E.*
AU  - Bakar, N.A.*
AU  - Wortmann, S.B.
AU  - Poerink, A.J.*
AU  - Grunewald, S.*
AU  - Crushell, E.*
AU  - Al-Gazali, L.*
AU  - de Vries, M.C.*
AU  - Mørkrid, L.*
AU  - Hertecant, J.*
AU  - Brocke Holmefjord, K.S.*
AU  - Kronn, D.*
AU  - Feigenbaum, A.*
AU  - Fingerhut, R.*
AU  - Wong, S.Y.*
AU  - van Scherpenzeel, M.*
AU  - Voermans, N.C.*
AU  - Lefeber, D.J.*
C1  - 60435
C2  - 49456
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 135-146
TI  - Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots.
JO  - Mol. Genet. Metab.
VL  - 131
IS  - 1-2
PB  - Academic Press Inc Elsevier Science
PY  - 2020
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - BACKGROUND: Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10). MATERIAL AND METHODS: Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail. RESULTS: For the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic MTO1 variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients. CONCLUSION: MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists.
AU  - O'Byrne, J.J.*
AU  - Tarailo-Graovac, M.*
AU  - Ghani, A.*
AU  - Champion, M.*
AU  - Deshpande, C.*
AU  - Dursun, A.*
AU  - Ozgul, R.K.*
AU  - Freisinger, P.*
AU  - Garber, I.*
AU  - Haack, T.B.*
AU  - Horvath, R.*
AU  - Barić, I.*
AU  - Husain, R.A.*
AU  - Kluijtmans, L.A.J.*
AU  - Kotzaeridou, U.*
AU  - Morris, A.A.*
AU  - Ross, C.J.*
AU  - Santra, S.*
AU  - Smeitink, J.*
AU  - Tarnopolsky, M.*
AU  - Wortmann, S.B.
AU  - Mayr, J.A.*
AU  - Brunner-Krainz, M.*
AU  - Prokisch, H.
AU  - Wasserman, W.W.*
AU  - Wevers, R.A.*
AU  - Engelke, U.F.*
AU  - Rodenburg, R.J.*
AU  - Ting, T.W.*
AU  - McFarland, R.*
AU  - Taylor, R.W.*
AU  - Salvarinova, R.*
AU  - van Karnebeek, C.D.M.*
C1  - 52731
C2  - 44226
SP  - 28-42
TI  - The genotypic and phenotypic spectrum of MTO1 deficiency.
JO  - Mol. Genet. Metab.
VL  - 123
IS  - 1
PY  - 2018
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Coenzyme Q10 (CoQ10) is an essential cofactor of the mitochondrial oxidative phosphorylation (OXPHOS) system and its deficiency has important implications for several inherited metabolic disorders of childhood. The biosynthesis of CoQ10 is a complicated process, which involves at least 12 different enzymes. One of the metabolic intermediates that are formed during CoQ10 biosynthesis is the molecule 6-demethoxyubiquinone (6-DMQ). This CoQ precursor is processed at the level of COQ7 and COQ9. We selected this metabolite as a marker substance for metabolic analysis of cell lines with inherited genetic defects (COQ2, COQ4, COQ7 and COQ9) or siRNA knockdown in CoQ biosynthesis enzymes using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). In COQ4, COQ7 and COQ9 deficient cell lines, we detected significantly elevated levels of 6-DMQ. This suggests a functional interplay of these proteins. However, additional siRNA studies demonstrated that elevated 6-DMQ levels are not an exclusive marker of the COQ7/COQ9 enzymatic step of CoQ10 biosynthesis but constitute a more general phenomenon that occurs in disorders impairing the function or stability of the CoQ-synthome. To further investigate the interdependence of CoQ10 biosynthesis enzyme expression, we performed immunoblotting in various cell lines with CoQ10 deficiency, indicating that COQ4, COQ7 and COQ9 protein expression levels are highly regulated depending on the underlying defect. Supplementation of cell lines with synthetic CoQ precursor compounds demonstrated beneficial effects of 2,4-dihydroxybenzoic acid in COQ7 and COQ9 deficiency. Moreover, vanillic acid selectively stimulated CoQ10 biosynthesis and improved cell viability in COQ9 deficiency. However, compounds tested in this study failed to rescue COQ4 deficiency.
AU  - Herebian, D.*
AU  - Seibt, A.*
AU  - Smits, S.H.J.*
AU  - Bünning, G.*
AU  - Freyer, C.*
AU  - Prokisch, H.
AU  - Karall, D.*
AU  - Wredenberg, A.*
AU  - Wedell, A.*
AU  - López, L.C.*
AU  - Mayatepek, E.*
AU  - Distelmaier, F.*
C1  - 51208
C2  - 43101
CY  - San Diego
SP  - 216-223
TI  - Detection of 6-demethoxyubiquinone in CoQ10 deficiency disorders: Insights into enzyme interactions and identification of potential therapeutics.
JO  - Mol. Genet. Metab.
VL  - 121
IS  - 3
PB  - Academic Press Inc Elsevier Science
PY  - 2017
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases.
AU  - Falk, M.J.*
AU  - Shen, L.*
AU  - Gonzalez, M.*
AU  - Leipzig, J.*
AU  - Lott, M.T.*
AU  - Stassen, A.P.*
AU  - Diroma, M.A.*
AU  - Navarro-Gomez, D.*
AU  - Yeske, P.*
AU  - Bai, R.*
AU  - Boles, R.G.*
AU  - Brilhante, V.*
AU  - Ralph, D.*
AU  - DaRe, J.T.*
AU  - Shelton, R.*
AU  - Terry, S.F.*
AU  - Zhang, Z.*
AU  - Copeland, W.C.*
AU  - van Oven, M.*
AU  - Prokisch, H.
AU  - Wallace, D.C.*
AU  - Attimonelli, M.*
AU  - Krotoski, D.*
AU  - Zuchner, S.*
AU  - Gai, X.*
C1  - 43030
C2  - 35978
CY  - San Diego
SP  - 388-396
TI  - Mitochondrial Disease Sequence Data Resource (MSeqDR): A global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities.
JO  - Mol. Genet. Metab.
VL  - 114
IS  - 3
PB  - Academic Press Inc Elsevier Science
PY  - 2015
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear.We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting.Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity.Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.
AU  - Banka, S.*
AU  - de Goede, C.G.*
AU  - Yue, W.W.*
AU  - Morris, A.A.*
AU  - von Bremen, B.*
AU  - Chandler, K.E.*
AU  - Feichtinger, R.G.*
AU  - Hart, C.*
AU  - Khan, N.*
AU  - Lunzer, V.*
AU  - Matakovic, L.*
AU  - Marquardt, T.*
AU  - Makowski, C.C.*
AU  - Prokisch, H.
AU  - Debus, O.*
AU  - Nosaka, K.*
AU  - Sonwalkar, H.*
AU  - Zimmermann, F.A.*
AU  - Sperl, W.J.*
AU  - Mayr, J.A.*
C1  - 42825
C2  - 35542
SP  - 301-306
TI  - Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations.
JO  - Mol. Genet. Metab.
VL  - 113
IS  - 4
PY  - 2014
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNAMet.Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing.All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C. >. T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases.
AU  - Haack, T.B.
AU  - Gorza, M.
AU  - Danhauser, K.
AU  - Mayr, J.A.*
AU  - Haberberger, B.*
AU  - Wieland, T.
AU  - Kremer, L.S.
AU  - Strecker, V.*
AU  - Graf, E.
AU  - Memari, Y.*
AU  - Ahting, U.*
AU  - Kopajtich, R.
AU  - Wortmann, S.B.*
AU  - Rodenburg, R.J.*
AU  - Kotzaeridou, U.*
AU  - Hoffmann, G.F.*
AU  - Sperl, W.*
AU  - Wittig, I.*
AU  - Wilichowski, E.*
AU  - Schottmann, G.*
AU  - Schuelke, M.*
AU  - Plecko, B.*
AU  - Stephani, U.*
AU  - Strom, T.M.
AU  - Meitinger, T.
AU  - Prokisch, H.
AU  - Freisinger, P.*
C1  - 30734
C2  - 33813
CY  - San Diego
SP  - 342-352
TI  - Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening.
JO  - Mol. Genet. Metab.
VL  - 111
IS  - 3
PB  - Academic Press Inc Elsevier Science
PY  - 2014
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.
AU  - Kraja, A.T.*
AU  - Chasman, D.I.*
AU  - North, K.E.*
AU  - Reiner, A.P.*
AU  - Yanek, L.R.*
AU  - Kilpeläinen, T.O.*
AU  - Smith, J.A.*
AU  - Dehghan, A.*
AU  - Dupuis, J.*
AU  - Johnson, A.D.*
AU  - Feitosa, M.F.*
AU  - Tekola-Ayele, F.*
AU  - Chu, A.Y.*
AU  - Nolte, I.M.*
AU  - Dastani, Z.*
AU  - Morris, A.*
AU  - Pendergrass, S.A.*
AU  - Sun, Y.V.*
AU  - Ritchie, M.D.*
AU  - Vaez, A.*
AU  - Lin, H.*
AU  - Ligthart, S.*
AU  - Marullo, L.*
AU  - Rohde, R.*
AU  - Shao, Y.*
AU  - Ziegler, M.A.*
AU  - Im, H.K.*
AU  - Cross Consortia Pleiotropy (XC-Pleiotropy) (*)
AU  - CHARGE Consortium (*)
AU  - GIANT Consortium (Albrecht, E.
AU  - Grallert, H.
AU  - Thorand, B.
AU  - Gieger, C.
AU  - Peters, A.
AU  - Wichmann, H.-E.
AU  - Illig, T.
AU  - Müller-Nurasyid, M.
AU  - Heid, I.M.)
AU  - Global Lipids Genetics Consortium (*)
AU  - MAGIC Consortium (*)
AU  - Global BPgen Consortium (Eyheramendy, S.
AU  - Döring, A.
AU  - Meitinger, T.
AU  - Pfeufer, A.)
AU  - ADIPOGen Consortium (*)
AU  - Women's Genome Health Study (*)
AU  - Howard University Family Study (*)
AU  - Schnabel, R.B.*
AU  - Jorgensen, T.*
AU  - Jorgensen, M.E.*
AU  - Hansen, T.*
AU  - Pedersen, O.*
AU  - Stolk, R.P.*
AU  - Snieder, H.*
AU  - Hofman, A.*
AU  - Uitterlinden, A.G.*
AU  - Franco, O.H.*
AU  - Ikram, M.A.*
AU  - Richards, J.B.*
AU  - Rotimi, C.N.*
AU  - Wilson, J.G.*
AU  - Lange, L.A.*
AU  - Ganesh, S.K.*
AU  - Nalls, M.*
AU  - Rasmussen-Torvik, L.J.*
AU  - Pankow, J.S.*
AU  - Coresh, J.*
AU  - Tang, W.*
AU  - Kao, W.H.L.*
AU  - Boerwinkle, E.*
AU  - Morrison, A.C.*
AU  - Ridker, P.M.*
AU  - Becker, D.M.*
AU  - Rotter, J.I.*
AU  - Kardia, S.L.R.*
AU  - Loos, R.J.F.*
AU  - Larson, M.G.*
AU  - Hsu, Y.H.*
AU  - Province, M.A.*
AU  - Tracy, R.*
AU  - Voight, B.F.*
AU  - Vaidya, D.*
AU  - O'Donnell, C.J.*
AU  - Benjamin, E.J.*
AU  - Alizadeh, B.Z.*
AU  - Prokopenko, I.*
AU  - Meigs, J.B.*
AU  - Borecki, I.B.*
C1  - 32402
C2  - 35044
CY  - San Diego
SP  - 317-338
TI  - Pleiotropic genes for metabolic syndrome and inflammation.
JO  - Mol. Genet. Metab.
VL  - 112
IS  - 4
PB  - Academic Press Inc Elsevier Science
PY  - 2014
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Mitochondria! complex I deficiency is a frequent biochemical condition, causing about one third of respiratory chain disorders. Partly due to the large number of genes necessary for its assembly and function only a small proportion of complex I deficiencies are yet confirmed at the molecular genetic level. Now, next generation sequencing approaches are applied to close the gap between biochemical definition and molecular diagnosis. Nevertheless such approaches result in a long list of novel rare single nucleotide variants. Identifying the causative mutations still remains challenging. Here we describe the identification and functional confirmation of novel NDUFS1 mutations using a cellular rescue-assay. Patient-derived complex I-defective fibroblast cell lines were transduced with wild type and mutant NDUFS1-cDNA and subsequently analyzed on the functional and protein level. We established the pathogenic nature of identified rare variants in four out of five disease alleles. This approach is a valuable add-on in disease genetics and it allows the analysis of the functional consequences of genetic variants in metabolic disorders.
AU  - Danhauser, K.
AU  - Iuso, A.
AU  - Haack, T.B.
AU  - Freisinger, P.*
AU  - Brockmann, K.*
AU  - Mayr, J.A.*
AU  - Meitinger, T.
AU  - Prokisch, H.
C1  - 6708
C2  - 29145
CY  - San Diego
SP  - 161-166
TI  - Cellular rescue-assay aids verification of causative DNA-variants in mitochondrial complex I deficiency.
JO  - Mol. Genet. Metab.
VL  - 103
IS  - 2
PB  - Acad. Press Inc. Elsevier Sc.
PY  - 2011
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - NKX2-3 SNP rs11190140 is associated with inflammatory bowel disease (IBD). The T allele is over-transmitted in IBD and the C allele represents a potential CpG methylation site. We hypothesize that genetic variation and/or methylation of SNP rs11190140 may play a role in NKX2-3 gene expression by affecting transcription factor binding. We studied 233 IBD cases and 250 unrelated healthy individuals from an IBD population from central Pennsylvania and performed genotype analyses of the genetic variation and methylation status analysis using PCR-based RFLP. For transcription factor binding, nuclear extracts from human B cells were incubated with biotin-labeled oligonucleotide sequences of the NKX2-3 promoter region containing the genetic variation of T, non-methylated C or methylated C at rs11190140, followed by biotin pull-down and Western blot analysis for transcription factors SP1, NFAT1, NF-κB, and ETS-1. In case-control analysis, the genetic variation was significantly associated with IBD (OR=0.503, 95% CI=0.330-0.764, p<0.001). Methylation status analyses revealed that the C allele is subject to modification by DNA methylation. transcription factor binding assay indicated distinct differential binding of NFAT1 to the NKX2-3 promoter sequence, with higher binding to those with non-methylated and methylated C than to T. The binding of NFAT1 to the NKX2-3 promoter region with rs1190140 was confirmed by ChIP assay. We speculate that the rs11190140 may regulate NKX2-3 expression and have a role in IBD pathogenesis.
AU  - John, G.
AU  - Hegarty, J.P.*
AU  - Yu, W.*
AU  - Berg, A.*
AU  - Pastor, D.M.*
AU  - Kelly, A.A.*
AU  - Wang, Y.*
AU  - Poritz, L.S.*
AU  - Schreiber, S.*
AU  - Koltun, W.A.*
AU  - Lin, Z.*
C1  - 6494
C2  - 28807
SP  - 174-179
TI  - NKX2-3 variant rs11190140 is associated with IBD and alters binding of NFAT.
JO  - Mol. Genet. Metab.
VL  - 104
IS  - 1-2
PB  - Elsevierr
PY  - 2011
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Respiratory chain enzymes consist of multiple subunits encoded either by the mitochondrial or by the nuclear genome. Recently the first X-chromosomal mutations in complex I deficient males have been described. Heterozygous female carriers did not seem to be affected. Here, we describe a girl initially presenting with mild muscular hypotonia, a moderate lactic acidosis and an increased beta-hydroxybutyrate/acetoacetate ratio. Biochemical investigations of a muscle biopsy revealed a deficiency in the amount and activity of complex I. Mutation screening of all structural subunits of complex I identified a heterozygous mutation c.94G>C, p.Gly32Arg in the X-chromosomal NDUFA1 gene. Analysis of the cDNA showed that 72% of the expressed mRNA was mutated in the muscle biopsy sample. Investigation of the X-inactivation pattern demonstrated that 74% of the paternally inherited allele was active in the muscle. This is the first report of an X-chromosomally inherited respiratory chain defect in a heterozygous female.
AU  - Mayr, J.A.*
AU  - Bodamer, O.*
AU  - Haack, T.B.
AU  - Zimmermann, F.A.*
AU  - Madignier, F.
AU  - Prokisch, H.
AU  - Rauscher, C.*
AU  - Koch, J.*
AU  - Sperl, W.*
C1  - 6750
C2  - 29206
SP  - 358-361
TI  - Heterozygous mutation in the X chromosomal NDUFA1 gene in a girl with complex I deficiency.
JO  - Mol. Genet. Metab.
VL  - 103
IS  - 4
PB  - Elsevier
PY  - 2011
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - The ileal fatty acid binding protein (FABP6) is known to be involved in enterohepatic bile acid metabolism. We have previously found a significant association between the rare allele of the FABP6 Thr79Met polymorphism and lower type 2 diabetes risk in a small case-control study (192 cases and 384 controls) embedded in the large EPIC-Potsdam cohort. A priori functional implication of the amino acid change was gained from in-silico analysis. In this study, we analysed an independent nested case-cohort including 543 incident type 2 diabetes cases from the EPIC-Potsdam cohort and a case-control study including 939 type 2 diabetes cases from KORA to confirm the association with type 2 diabetes and performed association analyses with quantitative disease-related measures in 2112 non-diabetic individuals. Homozygosity for the Met-allele was associated with lower risk of type 2 diabetes (EPIC-Potsdam: 0.70, P=0.04; KORA: 0.79, P=0.06) if adjusted for age, sex, body mass index (BMI), and waist circumference. The homozygous rare variant showed a significant interaction (P=0.006) with BMI. Relative risks in different categories (BMI <25, 25-30, and >30 kg/m(2)) showed an association exclusively in obese (BMI >30 kg/m(2)) individuals (combined risk ratio: 0.62, 95% CI 0.45-0.86). In non-diabetic individuals from the general adult population, no significant associations were observed with plasma total cholesterol, LDL-, and HDL-cholesterol, triglyceride, insulin and glucose concentration. In summary, we found evidence that the-putative functional-Thr79Met substitution of FABP6 confers a protective effect on type 2 diabetes in obese individuals.
AU  - Fisher, E.*
AU  - Grallert, H.
AU  - Klapper, M.*
AU  - Pfäfflin, A.*
AU  - Schrezenmeir, J.*
AU  - Illig, T.
AU  - Boeing, H.*
AU  - Döring, F.*
C1  - 709
C2  - 27238
SP  - 400-405
TI  - Evidence for the Thr79Met polymorphism of the ileal fatty acid binding protein (FABP6) to be associated with type 2 diabetes in obese individuals.
JO  - Mol. Genet. Metab.
VL  - 98
IS  - 4
PB  - Elsevier
PY  - 2009
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - The microsomal triglyceride transfer protein (MTTP) is a key regulator in the assembly and secretion of chylomicrons and very low density lipoprotein (VLDL) in the intestine and in liver. Associations between MTTP variants and traits of the metabolic syndrome are carried out in relatively small cohorts and are not consistent. We analysed MTTP polymorphisms in 7582 participants of the KORA study cohort. Seven htSNPs covering a 52 kb region of the MTTP locus and two cSNPs (I128T, H297Q) were selected. A MTTP haplotype containing the minor allele of H297Q showed a significant decrease of −0.636 (95% CI: −1.226, −0.046; p = 0.035) BMI units in females but not in males. In comparison to homozygous H-carriers for the major allele of the MTTP H297Q polymorphism, homozygous Q297Q carriers showed a significant decrease in BMI of −0.425 BMI units (95% CI: −0.74, −0.12; p = 0.007), in waist circumference of −0.990 cm (95% CI: 1.74, −0.24; p = 0.01) and in total cholesterol of −0.039 mmol/l (95% CI: −0.07, 0; p = 0.03). Heterozygous Q-carriers displayed a reduction in BMI of −0.183 BMI unit (95% CI: −0.33, −0.04; p = 0.012), in waist circumference of −0.45 cm (95% CI: 0.8, −0.1; p = 0.01) and in total cholesterol of −0.103 mmol/l (95% CI: −0.18, −0.03; p = 0.01). Gender stratified statistics revealed a significant reduction of −0.657 BMI units (95% CI: −1.14, −0.18; p = 0.007), −1.437 cm waist circumference (95% CI: −2.55, −0.32; p = 0.01) and −0.052 mmol/l total cholesterol (95% CI: −0.1, −0.01; p = 0.03) for females homozygous for the Q297Q polymorphism. Females carrying the Q-allele showed a decrease of −0.259 BMI unit (95% CI: −0.48, −0.04; p = 0.023), −0.662 cm waist circumference (95% CI: −1.18, −0.14; p = 0.01) and −0.111 mmol/l total cholesterol (95% CI: −0.21, −0.01; p = 0.03). Our association analysis in a large population based study cohort provides evidence that the minor allele of the MTTP H297Q polymorphism is associated with lower BMI, waist circumference and total cholesterol in females but not in males.
AU  - Böhme, M.*
AU  - Grallert, H.
AU  - Fischer, A.
AU  - Gieger, C.
AU  - Nitz, I.*
AU  - Heid, I.M.
AU  - Kohl, C.*
AU  - Wichmann, H.-E.
AU  - Illig, T.
AU  - Döring, F.*
C1  - 85
C2  - 26353
CY  - Amsterdam
SP  - 229-232
TI  - MTTP variants and body mass index, waist circumference and serum cholesterol level: Association analyses in 7582 participants of the KORA study cohort.
JO  - Mol. Genet. Metab.
VL  - 95
IS  - 4
PB  - Elsevier Inc.
PY  - 2008
SN  - 1096-7192
ER  - 

TY  - JOUR
AB  - Studies in rodent models demonstrated that the central cannabinoid receptor (Cnr1) mediates the orexigenic effects of cannabinoids. To analyze whether genetic variation in the cannabinoid receptor gene (CNR1) is implicated in human obesity, we initially genotyped 8 single nucleotide polymorphisms (SNPs) located in the 5' region (rs9353527, rs754387, rs6454676), intron 2 (rs806379, rs1535255), exon 3 (rs2023239), intron 3 (rs806370) and the coding region (rs1049353) in up to 364 German obesity trios (extremely obese child or adolescent and both parents). The transmission disequilibrium test (TDT) was negative for these SNPs (p>0.05). However, there was a slight trend towards preferential transmission of the A-allele of rs1049353 (p=0.12). We therefore genotyped this SNP in 235 independent German obesity families (at least two obese sibs and both parents) and in parallel screened the CNR1 coding region for sequence variations in 120 German extremely obese children and adolescents who mainly contributed to the initial trend observed for rs1049353. The trend for preferential transmission of the A-allele could not be substantiated (pedigree disequilibrium test, PDT p=0.15; A-allele less frequently transmitted). In the mutation screen we detected two rare variations, one novel non-conservative mutation (c.1256C>A; A419E) and the known variant 1419+1G>C. In addition, we confirmed the presence of rs1049353. As these variants could not explain the initial TDT, we conclude that there is no evidence for an association of CNR1 alleles with obesity in our study groups.
AU  - Müller, T.D.*
AU  - Reichwald, K.*
AU  - Wermter, A.K.*
AU  - Brönner, G.*
AU  - Nguyen, T.T.*
AU  - Friedel, S.*
AU  - Koberwitz, K.
AU  - Engeli, S.*
AU  - Lichtner, P.
AU  - Meitinger, T.
AU  - Schäfer, H.*
AU  - Hebebrand, J.*
AU  - Hinney, A.*
C1  - 4166
C2  - 24791
SP  - 429-434
TI  - No evidence for an involvement of variants in the cannabinoid receptor gene (CNR1) in obesity in German children and adolescents.
JO  - Mol. Genet. Metab.
VL  - 90
IS  - 4
PB  - Elsevier
PY  - 2007
SN  - 1096-7192
ER  -