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Biagosch CA, Vidali S, Faerberboeck M, et al. A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse. Mamm Genome. 2021;32(5):332-349doi: 10.1007/s00335-021-09875-3.
Biagosch, C. A., Vidali, S., Faerberboeck, M., Hensler, S. V., Becker, L., Amarie, O. V., Aguilar-Pimentel, 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., de Angelis, M. H., Janik, D., Wurst, W., Mayr, J. A., Klopstock, T., Meitinger, T., Prokisch, H., & Iuso, A. (2021). A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse. Mammalian genome : official journal of the International Mammalian Genome Society, 32(5), 332-349. https://doi.org/10.1007/s00335-021-09875-3
Biagosch, Caroline A, et al. "A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse." Mammalian genome : official journal of the International Mammalian Genome Society vol. 32,5 (2021): 332-349. doi: https://doi.org/10.1007/s00335-021-09875-3
Biagosch CA, Vidali S, Faerberboeck M, Hensler SV, Becker L, Amarie OV, Aguilar-Pimentel 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, de Angelis MH, Janik D, Wurst W, Mayr JA, Klopstock T, Meitinger T, Prokisch H, Iuso A. A comprehensive phenotypic characterization of a whole-body Wdr45 knock-out mouse. Mamm Genome. 2021 Oct;32(5):332-349. doi: 10.1007/s00335-021-09875-3. Epub 2021 May 27. PMID: 34043061; PMCID: PMC8458197.
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Mamm Genome. 2021 Oct;32(5):332-349. doi: 10.1007/s00335-021-09875-3. Epub 2021 May 27.

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

Mammalian genome : official journal of the International Mammalian Genome Society

Caroline A Biagosch, Silvia Vidali, Michael Faerberboeck, Svenja-Viola Hensler, Lore Becker, Oana V Amarie, Antonio Aguilar-Pimentel, Lillian Garrett, Tanja Klein-Rodewald, Birgit Rathkolb, Enrica Zanuttigh, Julia Calzada-Wack, Patricia da Silva-Buttkus, Jan Rozman, Irina Treise, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, Dirk Janik, Wolfgang Wurst, Johannes A Mayr, Thomas Klopstock, Thomas Meitinger, Holger Prokisch, Arcangela Iuso

Affiliations

  1. Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany.
  2. Institute of Neurogenomics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
  3. Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, 5020, Salzburg, Austria.
  4. Institute of Developmental Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
  5. German Mouse Clinic, Institute of Experimental Genetics Helmholtz Zentrum München, 85764, Neuherberg, Germany.
  6. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University Munich, 81377, Munich, Germany.
  7. German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
  8. Institute of Molecular Genetics of the Czech Academy of Sciences, Czech Centre for Phenogenomics, Prumyslova 595, Vestec, 252 50, Czechia.
  9. Chair of Experimental Genetics, TUM School of Life Sciences (SoLS), Technische Universität München, 85354, Freising, Germany.
  10. Chair of Developmental Genetics, TUM School of Life Sciences (SoLS), Technische Universität München, 85354 , Freising, Germany.
  11. Deutsches Zentrum Für Neurodegenerative Erkrankungen (DZNE) Site Munich, 81377, Munich, Germany.
  12. Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
  13. Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336, Munich, Germany.
  14. Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany. [email protected].
  15. Institute of Neurogenomics, Helmholtz Zentrum München, 85764, Neuherberg, Germany. [email protected].

PMID: 34043061 PMCID: PMC8458197 DOI: 10.1007/s00335-021-09875-3

Abstract

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.

© 2021. The Author(s).

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