PUBLICATION

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

Authors
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., Harlalka, G.V., Michaelides, M., Moore, A.T., Coban Akdemir, Z.H., Jhangiani, S., Lupski, J.R., Cremers, F.P.M., Qamar, R., Salman, A., Chilton, J., Self, J., Ayyagari, R., Kabir, F., Naeem, M.A., Ali, M., Akram, J., Sieving, P.A., Riazuddin, S., Baple, E.L., Riazuddin, S.A., Crosby, A.H., Hejtmancik, J.F.
ID
ZDB-PUB-180830-9
Date
2018
Source
PLoS Genetics   14: e1007504 (Journal)
Registered Authors
Hejtmancik, J. Fielding, Li, Lin, Nelson, Ralph, Ono, Fumihito
Keywords
none
MeSH Terms
  • Asian People/genetics
  • Cytoplasm/metabolism
  • Chloride Channels/genetics*
  • Chloride Channels/metabolism
  • Retinitis Pigmentosa/diagnosis
  • Retinitis Pigmentosa/genetics*
  • Mutation, Missense*
  • Mice
  • Animals
  • Retina/metabolism
  • HEK293 Cells
  • Eye Proteins/genetics
  • Eye Proteins/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Mice, Knockout
  • Pakistan
  • Humans
  • Retinal Rod Photoreceptor Cells/metabolism
  • Homozygote
  • Retinal Cone Photoreceptor Cells/metabolism
  • Cell Line
(all 22)
PubMed
30157172 Full text @ PLoS Genet.
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.
Genes / Markers
Figures
Figure Gallery (3 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO1-clcc1standard conditionsPrim-5
WT + MO1-clcc1standard conditionsPrim-25
WT + MO1-clcc1standard conditionsDay 4
WT + MO1-clcc1standard conditionsDay 4
WT + MO1-clcc1standard conditionsDay 4
WT + MO1-clcc1standard conditionsDay 4
WT + MO1-clcc1standard conditionsDay 4
WT + MO1-clcc1standard conditionsDay 4
clcc1nds201/nds201standard conditionsDay 5
clcc1nds201/nds201standard conditionsDay 5
1 - 10 of 17
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
nds201
    		Small Deletion
    1 - 1 of 1
    Show
    Human Disease / Model
    Sequence Targeting Reagents
    Fish
    Antibodies
    Orthology
    Engineered Foreign Genes
    No data available
    Mapping
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    Citation
    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., Harlalka, G.V., Michaelides, M., Moore, A.T., Coban Akdemir, Z.H., Jhangiani, S., Lupski, J.R., Cremers, F.P.M., Qamar, R., Salman, A., Chilton, J., Self, J., Ayyagari, R., Kabir, F., Naeem, M.A., Ali, M., Akram, J., Sieving, P.A., Riazuddin, S., Baple, E.L., Riazuddin, S.A., Crosby, A.H., Hejtmancik, J.F. (2018) Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. PLoS Genetics. 14:e1007504.