title: Mutations of CEP83 cause infantile nephronophthisis and intellectual disability.
abstract: Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Failler
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Department of Pediatric Nephrology, Necker Hospital, AP-HP, 75015 Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Krug
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Kwangsic
authors.initials: K
authors.lastname: Joo
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Lilya
authors.initials: L
authors.lastname: Belkacem
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Filhol
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Porath
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Braun
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Schueler
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Frigo
authors.affiliation: Genomic Core Facility, Imagine Institute, 75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Alibeu
authors.affiliation: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Masson
authors.affiliation: Department of Pediatrics, Toulouse Hospital, 31400 Toulouse, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Brochard
authors.affiliation: Department of Nephrology, Clemenceau Hospital, 14033 Caen, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Hurault de Ligny
authors.affiliation: Department of Pediatric Nephrology, Jeanne de Flandre Hospital, 59037 Lille, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Novo
authors.affiliation: Department of Pediatrics, American Memorial Hospital, 51092 Reims, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Pietrement
authors.affiliation: Medical Genetics Department, Istanbul Medical Faculty, İstanbul University 34093 Istanbul, Turkey.
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Department of Pediatric Nephrology, Necker Hospital, AP-HP, 75015 Paris, France; AP-HP, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Necker Hospital, 75015 Paris, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Salomon
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Department of Pediatric Nephrology, Necker Hospital, AP-HP, 75015 Paris, France.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48019, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; AP-HP, Genetic Department, Necker Hospital, 75015 Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benmerah
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France. Electronic address: sophie.saunier@inserm.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
mesh_terms: D000483:Alleles; D002490:Central Nervous System / Q000002:abnormalities; D002502:Centrioles / Q000235:genetics / Q000378:metabolism; D002675:Child, Preschool; D002923:Cilia / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009958:Orofaciodigital Syndromes / Q000235:genetics
chemical_list: C582178:CEP83 protein, human; D008869:Microtubule-Associated Proteins