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
  • Animals
  • Asians/genetics
  • Cell Line
  • Chloride Channels/genetics*
  • Chloride Channels/metabolism
  • Cytoplasm/metabolism
  • Eye Proteins/genetics
  • Eye Proteins/metabolism
  • HEK293 Cells
  • Homozygote
  • Humans
  • Mice
  • Mice, Knockout
  • Mutation, Missense*
  • Pakistan
  • Retina/metabolism
  • Retinal Cone Photoreceptor Cells/metabolism
  • Retinal Rod Photoreceptor Cells/metabolism
  • Retinitis Pigmentosa/diagnosis
  • Retinitis Pigmentosa/genetics*
  • Zebrafish/genetics
  • Zebrafish/metabolism
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
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes