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

Caroline A BiagoschSilvia VidaliMichael FaerberboeckSvenja-Viola HenslerLore BeckerOana Veronica AmarieJuan Antonio Aguilar-PimentelLillian GarrettTanja Klein-RodewaldBirgit RathkolbEnrica ZanuttighJulia Calzada-WackPatricia da Silva-ButtkusJan RozmanIrina TreiseHelmut FuchsValérie Gailus-DurnerMartin Hrabě de AngelisDirk JanikWolfgang WurstJohannes Adalbert MayrFlorentine RadelfahrThomas MeitingerHolger ProkischArcangela Iuso
Published in: Mammalian genome : official journal of the International Mammalian Genome Society (2021)
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.
Keyphrases
  • mouse model
  • copy number
  • white matter
  • systematic review
  • genome wide
  • oxidative stress
  • cerebral ischemia
  • signaling pathway
  • high fat diet induced
  • insulin resistance
  • iron deficiency
  • hearing loss