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Biagosch, C. ; Vidali, S. ; Faerberboeck, M. ; Hensler, S. ; Becker, L. ; Amarie, O.V. ; Aguilar-Pimentel, J.A. ; Garrett, L. ; Klein-Rodewald, T. ; Rathkolb, B. ; Zanuttigh, E. ; Calzada-Wack, J. ; da Silva Buttkus, P. ; Rozman, J. ; Treise, I. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Janik, D. ; Wurst, W. ; Mayr, J.A.* ; Klopstock, T.* ; Meitinger, T. ; Prokisch, H. ; Iuso, A.

A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse.

Mamm. Genome 32, 332-349 (2021)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mitochondrial Energy-metabolism; Autophagy; Mutations; Protocol; Shirpa; Dna; Neurodegeneration; Effectors; Proteins
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 0938-8990
e-ISSN 1432-1777
Zeitschrift Mammalian Genome
Quellenangaben Band: 32, Heft: 5, Seiten: 332-349 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort One New York Plaza, Suite 4600, New York, Ny, United States
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Institute of Human Genetics (IHG)
Institute of Developmental Genetics (IDG)
Institute of Experimental Genetics (IEG)
POF Topic(s) 30205 - Bioengineering and Digital Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30204 - Cell Programming and Repair
30201 - Metabolic Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503292-001
G-503200-001
G-500700-001
G-500500-001
G-500692-001
G-500600-001
G-500600-003
Förderungen Bundesministeriums fur Bildung und Forschung
NBIA Disorder Association grant
Projekt DEAL
DOI 10.1007/s00335-021-09875-3
WOS ID WOS:000655423000001
Scopus ID 85106764028
PubMed ID 34043061
Erfassungsdatum 2021-06-07
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