@article {615, title = {Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.}, journal = {PLoS Genet}, volume = {14}, year = {2018}, month = {2018 08}, pages = {e1007504}, 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.

}, keywords = {Animals, Asian Continental Ancestry Group, Cell Line, Chloride Channels, Cytoplasm, Eye Proteins, HEK293 Cells, Homozygote, Humans, Mice, Mice, Knockout, Mutation, Missense, Pakistan, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1007504}, author = {Li, Lin and Jiao, Xiaodong and D{\textquoteright}Atri, Ilaria and Ono, Fumihito and Nelson, Ralph and Chan, Chi-Chao and Nakaya, Naoki and Ma, Zhiwei and Ma, Yan and Cai, Xiaoying and Zhang, Longhua and Lin, Siying and Hameed, Abdul and Chioza, Barry A and Hardy, Holly and Arno, Gavin and Hull, Sarah and Khan, Muhammad Imran and Fasham, James and Harlalka, Gaurav V and Michaelides, Michel and Moore, Anthony T and Coban Akdemir, Zeynep Hande and Jhangiani, Shalini and Lupski, James R and Cremers, Frans P M and Qamar, Raheel and Salman, Ahmed and Chilton, John and Self, Jay and Ayyagari, Radha and Kabir, Firoz and Naeem, Muhammad Asif and Ali, Muhammad and Akram, Javed and Sieving, Paul A and Riazuddin, Sheikh and Baple, Emma L and Riazuddin, S Amer and Crosby, Andrew H and Hejtmancik, J Fielding} } @article {91, title = {Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death.}, journal = {Mol Genet Genomic Med}, volume = {4}, year = {2016}, month = {2016 Jan}, pages = {77-94}, abstract = {

BACKGROUND: Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30~years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown.

METHODS: We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds.

RESULTS: Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts (LOD~=~9.62). SNP-based fine mapping within the 9.5~Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg).

CONCLUSION: We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2.

}, issn = {2324-9269}, doi = {10.1002/mgg3.181}, author = {Boone, Philip M and Yuan, Bo and Gu, Shen and Ma, Zhiwei and Gambin, Tomasz and Gonzaga-Jauregui, Claudia and Jain, Mahim and Murdock, Todd J and White, Janson J and Jhangiani, Shalini N and Walker, Kimberly and Wang, Qiaoyan and Muzny, Donna M and Gibbs, Richard A and Hejtmancik, J Fielding and Lupski, James R and Posey, Jennifer E and Lewis, Richard A} }