A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse.
Journal
Mammalian genome : official journal of the International Mammalian Genome Society
ISSN: 1432-1777
Titre abrégé: Mamm Genome
Pays: United States
ID NLM: 9100916
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
16
02
2021
accepted:
11
05
2021
pubmed:
28
5
2021
medline:
9
2
2022
entrez:
27
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34043061
doi: 10.1007/s00335-021-09875-3
pii: 10.1007/s00335-021-09875-3
pmc: PMC8458197
doi:
Substances chimiques
Carrier Proteins
0
Wdr45 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
332-349Informations de copyright
© 2021. The Author(s).
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