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

TitleMutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.
Publication TypeJournal Article
Year of Publication2018
AuthorsLi, 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
JournalPLoS Genet
Date Published2018 Aug
KeywordsAnimals, 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

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.

Alternate JournalPLoS Genet
PubMed ID30157172
PubMed Central IDPMC6133373
Grant ListG1002279 / 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

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