期刊
PLOS GENETICS
卷 14, 期 8, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1007504
关键词
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资金
- National Eye Institute [R01EY021237-01, EY-000272]
- National Human Genome Research Institute (NHGRI)
- National Heart Lung and Blood Institute (NHLBI) [UM1 HG006542]
- National Natural Science Foundation for Young Scholars of China [81300801]
- National Natural Science Foundation of China [81670892]
- Shanghai Youth Eastern Scholar Grant [QD2015012]
- Medical Research Council UK (MRC) [G1002279]
- Newlife Foundation for Disabled Children [SG/15-16/12]
- Fight For Sight [2027]
- Rotterdamse Stichting Blindenbelangen
- Stichting voor Ooglijders
- Nelly Reef fund
- MRC [G1002279] Funding Source: UKRI
- Medical Research Council [G1002279] Funding Source: researchfish
- Newlife [SG/15-16/12] Funding Source: researchfish
- Fight for Sight [2027] Funding Source: researchfish
- NATIONAL EYE INSTITUTE [ZIAEY000272, R01EY021237] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [UM1HG006542] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [ZIANS002631] Funding Source: NIH RePORTER
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.
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