title: Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome.
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.
authors.affiliation: 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.
authors.forename: Estelle
authors.initials: E
authors.lastname: Colin
authors.affiliation: 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.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Huynh Cong
authors.affiliation: 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.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Mollet
authors.affiliation: Department of Biochemistry and Genetics, Angers University Hospital, 49933 Angers, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Guichet
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gribouval
authors.affiliation: 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.
authors.forename: Christelle
authors.initials: C
authors.lastname: Arrondel
authors.affiliation: 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.
authors.forename: Olivia
authors.initials: O
authors.lastname: Boyer
authors.affiliation: Department of Pathology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Daniel
authors.affiliation: 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.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.affiliation: Department of Pediatric Nephrology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey.
authors.forename: Zelal
authors.initials: Z
authors.lastname: Ekinci
authors.affiliation: Department of Pediatric Nephrology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tsimaratos
authors.affiliation: Department of Pediatric Neurology, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chabrol
authors.affiliation: 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.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Department of Genetics, Robert Debré Hospital, Assistance Publique - Hôpitaux de Paris and Université Paris Diderot, 75015 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: 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.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chevrollier
authors.affiliation: 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.
authors.forename: Naig
authors.initials: N
authors.lastname: Gueguen
authors.affiliation: 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.
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.affiliation: 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferré
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.affiliation: Departments of Neurology, Biochemistry, and Genetics, Limoges University Hospital, 87000 Limoges, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Richard
authors.affiliation: Departments of Neurology, Biochemistry, and Genetics, Limoges University Hospital, 87000 Limoges, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Funalot
authors.affiliation: Department of Genetics, Timone Hospital, Assistance Publique - Hôpitaux de Marseille, 13385 Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Moncla
authors.affiliation: 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.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: 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: corinne.antignac@inserm.fr.
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
mesh_terms: D000293:Adolescent; D001921:Brain / Q000503:physiopathology; D002460:Cell Line; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D003600:Cytosol / Q000378:metabolism; D059472:Exome / Q000235:genetics; D006551:Hernia, Hiatal / Q000235:genetics* / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007678:Kidney Glomerulus / Q000503:physiopathology; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D008958:Models, Molecular; D009154:Mutation; D009401:Nephrosis / Q000235:genetics* / Q000503:physiopathology; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000503:physiopathology; D050199:Podocytes; D021381:Protein Transport; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D064047:Spindle Poles / Q000378:metabolism
chemical_list: D011506:Proteins; C000595586:WDR73 protein, human