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, Sheikh Amer Riazuddin, Andrew H. Crosby, J. Fielding Hejtmancik

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article numbere1007504
JournalPLoS Genetics
Volume14
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

chloride channels
Chloride Channels
Retinitis Pigmentosa
cones (retina)
Zebrafish
mutation
Rod Opsins
Cone Opsins
chloride
Danio rerio
Messenger RNA
Mutation
Vertebrate Photoreceptor Cells
apoptosis
Mutant Proteins
Fertilization
Small Interfering RNA
rods (retina)
Retina
Chlorides

ASJC Scopus subject areas

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

Cite this

Li, L., Jiao, X., D’Atri, I., Ono, F., Nelson, R., Chan, C. C., ... 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

Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. / Li, Lin; Jiao, Xiaodong; D’Atri, Ilaria; Ono, Fumihito; Nelson, Ralph; Chan, Chi Chao; Nakaya, Naoki; Ma, Zhiwei; Ma, Yan; Cai, Xiaoying; Zhang, Longhua; Lin, Siying; Hameed, Abdul; Chioza, Barry A.; Hardy, Holly; Arno, Gavin; Hull, Sarah; Khan, Muhammad Imran; Fasham, James; Harlalka, Gaurav V.; Michaelides, Michel; Moore, Anthony T.; Coban Akdemir, Zeynep Hande; Jhangiani, Shalini; Lupski, James R.; Cremers, Frans P.M.; Qamar, Raheel; Salman, Ahmed; Chilton, John; Self, Jay; Ayyagari, Radha; Kabir, Firoz; Naeem, Muhammad Asif; Ali, Muhammad; Akram, Javed; Sieving, Paul A.; Riazuddin, Sheikh; Baple, Emma L.; Riazuddin, Sheikh Amer; Crosby, Andrew H.; Hejtmancik, J. Fielding.

In: PLoS Genetics, Vol. 14, No. 8, e1007504, 01.08.2018.

Research output: Contribution to journalArticle

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
Li, Lin ; Jiao, Xiaodong ; D’Atri, Ilaria ; Ono, Fumihito ; Nelson, Ralph ; Chan, Chi Chao ; Nakaya, Naoki ; Ma, Zhiwei ; Ma, Yan ; Cai, Xiaoying ; Zhang, Longhua ; Lin, Siying ; Hameed, Abdul ; Chioza, Barry A. ; Hardy, Holly ; Arno, Gavin ; Hull, Sarah ; Khan, Muhammad Imran ; Fasham, James ; Harlalka, Gaurav V. ; Michaelides, Michel ; Moore, Anthony T. ; Coban Akdemir, Zeynep Hande ; Jhangiani, Shalini ; Lupski, James R. ; Cremers, Frans P.M. ; Qamar, Raheel ; Salman, Ahmed ; Chilton, John ; Self, Jay ; Ayyagari, Radha ; Kabir, Firoz ; Naeem, Muhammad Asif ; Ali, Muhammad ; Akram, Javed ; Sieving, Paul A. ; Riazuddin, Sheikh ; Baple, Emma L. ; Riazuddin, Sheikh Amer ; Crosby, Andrew H. ; Hejtmancik, J. Fielding. / Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. In: PLoS Genetics. 2018 ; Vol. 14, No. 8.
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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.",
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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, Sheikh Amer

AU - Crosby, Andrew H.

AU - Hejtmancik, J. Fielding

PY - 2018/8/1

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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.

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