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Am J Hum Genet. 2014 Dec 4;95(6):637-48. doi: 10.1016/j.ajhg.2014.10.011. Epub 2014 Nov 13.

Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome.

Author information

  • 1Department of Biochemistry and Genetics, Angers University Hospital, 49933 Angers, France; Centre National de la Recherche Scientifique 6214 and Institut National de la Santé et de la Recherche Médicale 1083, Université Nantes Angers Le Mans, 49000 Angers, France.
  • 2Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
  • 3Department of Biochemistry and Genetics, Angers University Hospital, 49933 Angers, France.
  • 4Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France; Department of Pediatric Nephrology, Necker Hospital, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
  • 5Department of Pathology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
  • 6Department of Pediatric Nephrology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey.
  • 7Department of Pediatric Nephrology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
  • 8Department of Pediatric Neurology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
  • 9Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France; Department of Pediatric Radiology, Necker Hospital, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
  • 10Department of Genetics, Robert Debré Hospital, Assistance Publique - Hôpitaux de Paris and Université Paris Diderot, 75015 Paris, France.
  • 11Departments of Neurology, Biochemistry, and Genetics, Limoges University Hospital, 87000 Limoges, France.
  • 12Department of Genetics, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
  • 13Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France; Department of Genetics, Necker Hospital, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France. Electronic address: corinne.antignac@inserm.fr.

Abstract

Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.

Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PMID:
25466283
[PubMed - indexed for MEDLINE]
PMCID:
PMC4259970
Free PMC Article
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