Mutations of CEP83 Cause Infantile Nephronophthisis and Intellectual Disability

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• 作者：Marion Failler¹ ; ² ; ¹⁶ ; Heon Yung Gee³ ; ¹⁶ ; Pauline Krug¹ ; ² ; ⁴ ; Kwangsic Joo⁵ ; Jan Halbritter³ ; Lilya Belkacem¹ ; ² ; Emilie Filhol¹ ; ² ; Jonathan D. Porath³ ; Daniela A. Braun³ ; Markus Schueler³ ; Amandine Frigo¹ ; ² ; Olivier Alibeu⁶ ; Cé ; cile Masson² ; Karine Brochard⁷ ; Bruno Hurault de Ligny⁸ ; Robert Novo⁹ ; Christine Pietrement¹⁰ ; Hulya Kayserili¹¹ ; Ré ; mi Salomon¹ ; ⁴ ; ¹² ; Marie-Claire Gubler¹ ; ² ; ⁴ ; Edgar A. Otto¹³ ; Corinne Antignac¹ ; ² ; ¹⁴ ; Joon Kim⁵ ; Alexandre Benmerah¹ ; ² ; Friedhelm Hildebrandt³ ; ¹⁵ ; ¹⁷ ; ^{friedhelm.hildebrandt@childrens.harvard.edu" class="auth_mail} ; Sophie Saunier¹ ; ² ; ¹⁷ ; ^{sophie.saunier@inserm.fr" class="auth_mail}
• 刊名：The American Journal of Human Genetics
• 出版年：5 June 2014
• 年：2014
• 卷：94
• 期：6
• 页码：905-914
• 全文大小：2965 K

文摘

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.