Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa

by Lin Li, Xiaodong Jiao, Ilaria D ’Atri, Fumihito Ono, Ralph Nelson, Chi-Chao Chan, Naoki Nakaya, Zhiwei Ma, Yan Ma, Xiaoying Cai, Longhua Zhang, Siying Lin, Abdul Hameed, Barry A. Chioza, Holly Hardy, Gavin Arno, Sarah Hull, Muhammad Imran Khan, James Fasham, Gaurav V. Harlalka, Michel Michaelides, Anthony T. Moore, Zeynep Hande Coban Akdemir, Shalini Jhangiani, James R. Lupski, Frans P. M. Cremers, Raheel Qamar, Ahmed Salman, John Chilton, Jay Self, Radha Ayyagari, Firoz Kabir, Muhammad Asif Naeem, Muhammad Ali, Javed Akram, Paul A. Sieving, Sheikh Riazuddin, Emma L. Baple, S. Amer Riazuddin, Andrew H. Crosby, J. Fielding Hejtmancik We identified a homozygous missense alteration (c.75C>A, p.D25E) inCLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown ofCLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild typeCLCC1 mRNA.Clcc1+/- KO mice showed decreased ERGs and photoreceptor number...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research