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.

• Authors: Lin Li, Xiaodong Jiao, Ilaria D'Atri, Fumihito Ono, Ralph Nelson, Chi-Chao Chan, Naoki Nakaya, Zhiwei Ma, Yan Ma, Xiaoying Cai, Longhua Zhang, Siying Lin, Abdul Hameed, Barry A Chioza, Holly Hardy, Gavin Arno, Sarah Hull, Muhammad Imran Khan, James Fasham, Gaurav V Harlalka, Michel Michaelides, Anthony T Moore, Zeynep Hande Coban Akdemir, Shalini Jhangiani, James R Lupski, Frans P M Cremers, Raheel Qamar, Ahmed Salman, John Chilton, Jay Self, Radha Ayyagari, Firoz Kabir, Muhammad Asif Naeem, Muhammad Ali, Javed Akram, Paul A Sieving, Sheikh Riazuddin, Emma L Baple, S Amer Riazuddin, Andrew H Crosby, J Fielding Hejtmancik
• Journal: PLoS genetics (PLoS Genet) Vol. 14 Issue 8 Pg. e1007504 (08 2018) ISSN: 1553-7404 [Electronic] United States
• PMID: 30157172 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CLCC1 protein, human
• Chloride Channels
• Clcc1 protein, mouse
• Eye Proteins

Topics

• Animals
• Asian People (genetics)
• Cell Line
• Chloride Channels (genetics, metabolism)
• Cytoplasm (metabolism)
• Eye Proteins (genetics, metabolism)
• HEK293 Cells
• Homozygote
• Humans
• Mice
• Mice, Knockout
• Mutation, Missense
• Pakistan
• Retina (metabolism)
• Retinal Cone Photoreceptor Cells (metabolism)
• Retinal Rod Photoreceptor Cells (metabolism)
• Retinitis Pigmentosa (diagnosis, genetics)
• Zebrafish (genetics, metabolism)