| Title | Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | Li, L, Jiao, X, D'Atri, I, Ono, F, Nelson, R, Chan, C-C, Nakaya, N, Ma, Z, Ma, Y, Cai, X, Zhang, L, Lin, S, Hameed, A, Chioza, BA, Hardy, H, Arno, G, Hull, S, Khan, MImran, Fasham, J, Harlalka, GV, Michaelides, M, Moore, AT, Akdemir, ZHande Coba, Jhangiani, S, Lupski, JR, Cremers, FPM, Qamar, R, Salman, A, Chilton, J, Self, J, Ayyagari, R, Kabir, F, Naeem, MAsif, Ali, M, Akram, J, Sieving, PA, Riazuddin, S, Baple, EL, S Riazuddin, A, Crosby, AH, J Hejtmancik, F |
| Journal | PLoS Genet |
| Volume | 14 |
| Issue | 8 |
| Pagination | e1007504 |
| Date Published | 2018 Aug |
| ISSN | 1553-7404 |
| Keywords | Animals, Asian People, Cell Line, Chloride Channels, Cytoplasm, Eye Proteins, HEK293 Cells, Homozygote, Humans, Mice, Mice, Knockout, Mutation, Missense, Pakistan, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, Zebrafish |
| Abstract | We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, 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 of CLCC1 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 type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells. |
| DOI | 10.1371/journal.pgen.1007504 |
| Alternate Journal | PLoS Genet |
| PubMed ID | 30157172 |
| PubMed Central ID | PMC6133373 |
| Grant List | G1002279 / MRC_ / Medical Research Council / United Kingdom R01 EY021237 / EY / NEI NIH HHS / United States 209083/Z/17/Z / / Wellcome Trust / United Kingdom UM1 HG006542 / HG / NHGRI NIH HHS / United States |