Li, L;
Jiao, X;
D'Atri, I;
Ono, F;
Nelson, R;
Chan, C-C;
Nakaya, N;
... Hejtmancik, JF; + view all
(2018)
Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.
PLoS Genetics
, 14
(8)
, Article e1007504. 10.1371/journal.pgen.1007504.
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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.
| Type: | Article |
|---|---|
| Title: | Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1007504 |
| Publisher version: | https://doi.org/10.1371/journal.pgen.1007504 |
| Language: | English |
| Additional information: | : This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 1.0 Universal (CC0 1.0) public domain dedication. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, ISOLATED FROG RETINA, ENDOPLASMIC-RETICULUM, ER STRESS, GENE, DYSTROPHIES, ZEBRAFISH, DEGENERATION, EXPRESSION, ABCA4, DNA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10056583 |
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