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

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.

SUBMITTER: Li L

PROVIDER: S-EPMC6133373 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Li Lin L Jiao Xiaodong X D'Atri Ilaria I Ono Fumihito F Nelson Ralph R Chan Chi-Chao CC Nakaya Naoki N Ma Zhiwei Z Ma Yan Y Cai Xiaoying X Zhang Longhua L Lin Siying S Hameed Abdul A Chioza Barry A BA Hardy Holly H Arno Gavin G Hull Sarah S Khan Muhammad Imran MI Fasham James J Harlalka Gaurav V GV Michaelides Michel M Moore Anthony T AT Coban Akdemir Zeynep Hande ZH Jhangiani Shalini S Lupski James R JR Cremers Frans P M FPM Qamar Raheel R Salman Ahmed A Chilton John J Self Jay J Ayyagari Radha R Kabir Firoz F Naeem Muhammad Asif MA Ali Muhammad M Akram Javed J Sieving Paul A PA Riazuddin Sheikh S Baple Emma L EL Riazuddin S Amer SA Crosby Andrew H AH Hejtmancik J Fielding JF

PLoS genetics 20180829 8

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 ...[more]

PMID: 30157172

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Project description:PURPOSE: Retinitis pigmentosa (RP; MIM 268000) is a hereditary disease characterized by poor night vision and progressive loss of photoreceptors, eventually leading to blindness. This degenerative process primarily affects peripheral vision due to the loss of rods. Autosomal recessive RP (arRP) is clinically and genetically heterogeneous. It has been associated with mutations in different genes, including CRB1 (crumbs homolog 1). The aim of this study was to determine the causative gene in a Tunisian patient with arRP born to non-consanguineous parents. METHODS: Four accessible family members were included. They underwent full ophthalmic examination with best-corrected Snellen visual acuity, fundus photography and fluorescein angiography. Haplotype analysis was used to evaluate homozygosity in the family to 20 arRP loci. All exons and intron-exon junctions of candidate genes not excluded by haplotype analysis were PCR amplified and directly sequenced. RESULTS: The proband was a 43-year-old female patient. Best-corrected visual acuity was 20/63 (right eye) and 20/80 (left eye). Visual loss began during the third decade. Funduscopic examination and fluorescein angiography revealed typical advanced RP changes with bone spicule-like pigment deposits in the posterior pole and the midperiphery along with retinal atrophy, narrowing of the vessels, and waxy optic discs. Haplotype analysis revealed homozygosity with microsatellite markers D1S412 and D1S413 on chromosome 1q31.3. These markers flanked CRB1. Our results excluded linkage of all the other arRP loci/genes tested. Sequencing of the 12 coding exons and splice sites of CRB1 disclosed a homozygous missense mutation in exon 7 at nucleotide c. 2291G>A, resulting in an arginine to histidine substitution (p.R764H). CONCLUSIONS: R764H is a novel mutation associated with CRB1-related arRP. Previously, an R764C mutation was reported. Extending the mutation spectrum of CRB1 with additional families is important for genotype-phenotype correlations and characterization of the scope of mutation.

Dataset Information

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

Publications

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

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