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

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

  • Am J Hum Genet. 2014 Dec 4;95(6):637-48. doi: 10.1016/j.ajhg.2014.10.011.
Estelle Colin 1,  Evelyne Huynh Cong 2,  Géraldine Mollet 2,  Agnès Guichet 3,  Olivier Gribouval 2,  Christelle Arrondel 2,  Olivia Boyer 4,  Laurent Daniel 5,  Marie-Claire Gubler 4,  Zelal Ekinci 6,  Michel Tsimaratos 7,  Brigitte Chabrol 8,  Nathalie Boddaert 9,  Alain Verloes 10,  Arnaud Chevrollier 1,  Naig Gueguen 1,  Valérie Desquiret-Dumas 1,  Marc Ferré 1,  Vincent Procaccio 1,  Laurence Richard 11,  Benoit Funalot 11,  Anne Moncla 12,  Dominique Bonneau 1,  Corinne Antignac 13
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Institut 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.
  • 3 Department of Biochemistry and Genetics, Angers University Hospital, 49933 Angers, France.
  • 4 Institut 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.
  • 5 Department of Pathology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
  • 6 Department of Pediatric Nephrology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey.
  • 7 Department of Pediatric Nephrology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
  • 8 Department of Pediatric Neurology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
  • 9 Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France; Department of Pediatric Radiology, Necker Hospital, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
  • 10 Department of Genetics, Robert Debré Hospital, Assistance Publique - Hôpitaux de Paris and Université Paris Diderot, 75015 Paris, France.
  • 11 Departments of Neurology, Biochemistry, and Genetics, Limoges University Hospital, 87000 Limoges, France.
  • 12 Department of Genetics, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
  • 13 Institut 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: [email protected].
PMID: 25466283 DOI: 10.1016/j.ajhg.2014.10.011
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.

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