Mutations of CEP83 cause infantile nephronophthisis and intellectual disability

Am J Hum Genet. 2014 Jun 5;94(6):905-14. doi: 10.1016/j.ajhg.2014.05.002.

Marion Failler ¹, Heon Yung Gee ², Pauline Krug ³, Kwangsic Joo ⁴, Jan Halbritter ², Lilya Belkacem ¹, Emilie Filhol ¹, Jonathan D Porath ², Daniela A Braun ², Markus Schueler ², Amandine Frigo ¹, Olivier Alibeu ⁵, Cécile Masson ⁶, Karine Brochard ⁷, Bruno Hurault de Ligny ⁸, Robert Novo ⁹, Christine Pietrement ¹⁰, Hulya Kayserili ¹¹, Rémi Salomon ¹², Marie-Claire Gubler ³, Edgar A Otto ¹³, Corinne Antignac ¹⁴, Joon Kim ⁴, Alexandre Benmerah ¹, Friedhelm Hildebrandt ¹⁵, Sophie Saunier ¹⁶

Affiliations

1 INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
2 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3 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.
4 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
5 Genomic Core Facility, Imagine Institute, 75015 Paris, France.
6 Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
7 Department of Pediatrics, Toulouse Hospital, 31400 Toulouse, France.
8 Department of Nephrology, Clemenceau Hospital, 14033 Caen, France.
9 Department of Pediatric Nephrology, Jeanne de Flandre Hospital, 59037 Lille, France.
10 Department of Pediatrics, American Memorial Hospital, 51092 Reims, France.
11 Medical Genetics Department, Istanbul Medical Faculty, İstanbul University 34093 Istanbul, Turkey.
12 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.
13 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48019, USA.
14 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.
15 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.
16 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.

PMID: 24882706 DOI: 10.1016/j.ajhg.2014.05.002

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.