Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa PMID: 30157172

Target-related Cytokines

2026-09-23

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

PLoS Genet. 2018 Aug 29;14(8):e1007504. doi: 10.1371/journal.pgen.1007504.

Lin Li ¹ ² , Xiaodong Jiao ² , Ilaria D'Atri ³ , Fumihito Ono ⁴ ⁵ , Ralph Nelson ⁶ , Chi-Chao Chan ⁷ , Naoki Nakaya ⁸ , Zhiwei Ma ² , Yan Ma ² , Xiaoying Cai ⁹ , Longhua Zhang ⁹ , Siying Lin ³ , Abdul Hameed ³ ¹⁰ , Barry A Chioza ³ , Holly Hardy ³ , Gavin Arno ¹¹ ¹² , Sarah Hull ¹¹ ¹² , Muhammad Imran Khan ¹³ , James Fasham ³ ¹⁴ , Gaurav V Harlalka ³ , Michel Michaelides ¹¹ ¹² , Anthony T Moore ¹¹ ¹² ¹⁵ , Zeynep Hande Coban Akdemir ¹⁶ , Shalini Jhangiani ¹⁷ , James R Lupski ¹⁶ ¹⁷ ¹⁸ ¹⁹ , Frans P M Cremers ²⁰ , Raheel Qamar ¹³ , Ahmed Salman ²¹ , John Chilton ³ , Jay Self ²¹ , Radha Ayyagari ²² , Firoz Kabir ²³ ²⁴ , Muhammad Asif Naeem ²³ , Muhammad Ali ²³ ²⁴ , Javed Akram ²⁵ ²⁶ , Paul A Sieving ²⁷ , Sheikh Riazuddin ²³ ²⁵ ²⁶ , Emma L Baple ³ ¹⁴ , S Amer Riazuddin ²³ ²⁴ , Andrew H Crosby ³ , J Fielding Hejtmancik ²

Affiliations

1. Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China.
2. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
3. RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Exeter, United Kingdom.
4. Section on Model Synaptic Systems, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.
5. Department of Physiology, Osaka Medical College, Takatsuki, Japan.
6. Unit on Neural Circuits, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
7. Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
8. Section of Molecular Mechanisms of Glaucoma, Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
9. School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, P.R. China.
10. Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
11. Institute of Ophthalmology, University College London, London, United Kingdom.
12. Department of Biosciences, Moorfields Eye Hospital, London, United Kingdom.
13. Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
14. Department of Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, United Kingdom.
15. Ophthalmology Department, UCSF School of Medicine, San Francisco, California, United States of America.
16. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
17. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
18. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
19. Texas Children's Hospital, Houston, Texas, United States of America.
20. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
21. Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
22. Shiley Eye Institute, University of California San Diego, La Jolla, California, United States of America.
23. National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
24. The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
25. Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.
26. National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
27. National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

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.