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 | |
| State | Published - Aug 1 2018 |
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ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
Cite this
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 journal › Article
}
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, Sheikh Amer
AU - Crosby, Andrew H.
AU - Hejtmancik, J. Fielding
PY - 2018/8/1
Y1 - 2018/8/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85053076236&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053076236&partnerID=8YFLogxK
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 -