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

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

doi:10.1371/journal.pgen.1007504

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

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. HarlalkaMichel 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

School of Medicine

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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.

Original language	English (US)
Article number	e1007504
Journal	PLoS genetics
Volume	14
Issue number	8
DOIs	https://doi.org/10.1371/journal.pgen.1007504
State	Published - Aug 2018

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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Li, L., Jiao, X., D’Atri, I., Ono, F., Nelson, R., Chan, C. C., Nakaya, N., Ma, Z., Ma, Y., Cai, X., Zhang, L., Lin, S., Hameed, A., Chioza, B. A., Hardy, H., Arno, G., Hull, S., Khan, M. I., Fasham, J., ... Hejtmancik, J. F. (2018). Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. PLoS genetics, 14(8), [e1007504]. https://doi.org/10.1371/journal.pgen.1007504

Li, L, Jiao, X, D’Atri, I, Ono, F, Nelson, R, Chan, CC, Nakaya, N, Ma, Z, Ma, Y, Cai, X, Zhang, L, Lin, S, Hameed, A, Chioza, BA, Hardy, H, Arno, G, Hull, S, Khan, MI, Fasham, J, Harlalka, GV, Michaelides, M, Moore, AT, Coban Akdemir, ZH, Jhangiani, S, Lupski, JR, Cremers, FPM, Qamar, R, Salman, A, Chilton, J, Self, J, Ayyagari, R, Kabir, F, Naeem, MA, Ali, M, Akram, J, Sieving, PA, Riazuddin, S, Baple, EL, Riazuddin, SA, Crosby, AH & Hejtmancik, JF 2018, 'Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa', PLoS genetics, vol. 14, no. 8, e1007504. https://doi.org/10.1371/journal.pgen.1007504

@article{e581461d49d4428bab6150e0e1390b8e,

title = "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.",

author = "Lin Li and Xiaodong Jiao and Ilaria D{\textquoteright}Atri and Fumihito Ono and Ralph Nelson and Chan, {Chi Chao} and Naoki Nakaya and Zhiwei Ma and Yan Ma and Xiaoying Cai and Longhua Zhang and Siying Lin and Abdul Hameed and Chioza, {Barry A.} and Holly Hardy and Gavin Arno and Sarah Hull and Khan, {Muhammad Imran} and James Fasham and Harlalka, {Gaurav V.} and Michel Michaelides and Moore, {Anthony T.} and {Coban Akdemir}, {Zeynep Hande} and Shalini Jhangiani and Lupski, {James R.} and Cremers, {Frans P.M.} and Raheel Qamar and Ahmed Salman and John Chilton and Jay Self and Radha Ayyagari and Firoz Kabir and Naeem, {Muhammad Asif} and Muhammad Ali and Javed Akram and Sieving, {Paul A.} and Sheikh Riazuddin and Baple, {Emma L.} and Riazuddin, {S. Amer} and Crosby, {Andrew H.} and Hejtmancik, {J. Fielding}",

note = "Funding Information: We are grateful to the following sponsors and funders: National Eye Institute (R01EY021237-01 to SAR)(Project EY-000272 to JFH), National Human Genome Research Institute (NHGRI), National Heart Lung and Blood Institute (NHLBI) (UM1 HG006542 to JRL), National Natural Science Foundation for Young Scholars of China (81300801 to LL), National Natural Science Foundation of China (81670892 to LL) Shanghai Youth Eastern Scholar Grant (QD2015012 to LL), Medical Research Council UK (MRC)(G1002279 to AHC), the Newlife Foundation for Disabled Children (SG/15-16/12 to AHC and ELB), Fight For Sight (2027 to AHC and ELB), Rotterdamse Stichting Blindenbelangen, Stichting voor Ooglijders, Nelly Reef fund—(to FPMC amd MIK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2018, Public Library of Science. All rights reserved.",

year = "2018",

month = aug,

doi = "10.1371/journal.pgen.1007504",

language = "English (US)",

volume = "14",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "8",

}

TY - JOUR

T1 - Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa

AU - Li, Lin

AU - Jiao, Xiaodong

AU - D’Atri, Ilaria

AU - Ono, Fumihito

AU - Nelson, Ralph

AU - Chan, Chi Chao

AU - Nakaya, Naoki

AU - Ma, Zhiwei

AU - Ma, Yan

AU - Cai, Xiaoying

AU - Zhang, Longhua

AU - Lin, Siying

AU - Hameed, Abdul

AU - Chioza, Barry A.

AU - Hardy, Holly

AU - Arno, Gavin

AU - Hull, Sarah

AU - Khan, Muhammad Imran

AU - Fasham, James

AU - Harlalka, Gaurav V.

AU - Michaelides, Michel

AU - Moore, Anthony T.

AU - Coban Akdemir, Zeynep Hande

AU - Jhangiani, Shalini

AU - Lupski, James R.

AU - Cremers, Frans P.M.

AU - Qamar, Raheel

AU - Salman, Ahmed

AU - Chilton, John

AU - Self, Jay

AU - Ayyagari, Radha

AU - Kabir, Firoz

AU - Naeem, Muhammad Asif

AU - Ali, Muhammad

AU - Akram, Javed

AU - Sieving, Paul A.

AU - Riazuddin, Sheikh

AU - Baple, Emma L.

AU - Riazuddin, S. Amer

AU - Crosby, Andrew H.

AU - Hejtmancik, J. Fielding

N1 - Funding Information: We are grateful to the following sponsors and funders: National Eye Institute (R01EY021237-01 to SAR)(Project EY-000272 to JFH), National Human Genome Research Institute (NHGRI), National Heart Lung and Blood Institute (NHLBI) (UM1 HG006542 to JRL), National Natural Science Foundation for Young Scholars of China (81300801 to LL), National Natural Science Foundation of China (81670892 to LL) Shanghai Youth Eastern Scholar Grant (QD2015012 to LL), Medical Research Council UK (MRC)(G1002279 to AHC), the Newlife Foundation for Disabled Children (SG/15-16/12 to AHC and ELB), Fight For Sight (2027 to AHC and ELB), Rotterdamse Stichting Blindenbelangen, Stichting voor Ooglijders, Nelly Reef fund—(to FPMC amd MIK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2018, Public Library of Science. All rights reserved.

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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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U2 - 10.1371/journal.pgen.1007504

DO - 10.1371/journal.pgen.1007504

M3 - Article

C2 - 30157172

AN - SCOPUS:85053076236

VL - 14

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 8

M1 - e1007504

ER -

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

Abstract

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