(2020) identified a heterozygous c.1658A-G transition (c.1658A-G, NM_001286.4) in the CLCN6 gene, resulting in a tyr553-to-cys (Y553C) substitution at a highly conserved residue in the transmembrane domain. In 3 unrelated children with childhood-onset neurodegeneration with hypotonia, respiratory insufficiency, and brain imaging abnormalities (CONRIBA 619173), Polovitskaya et al. Although patient-derived fibroblasts did not showed enlarged vacuoles, the authors speculated that neuronal cells, which express CLCN6, may demonstrate these abnormalities and may also have altered lysosomal function. Bafilomycin treatment abrogated vacuole generation, indicating that H(+)-driven Cl- accumulation osmotically drives vesicle enlargement. HeLa cells transfected with the mutant protein developed abnormally large cytoplasmic vesicles, likely due to enhanced fusion, that were poorly acidified. Unlike wildtype, mutant channels did not show decreased activity in the presence of low pH, indicating insensitivity to low pH, which further contributes to a gain-of-function effect. Electrophysiologic studies in CHO cells transfected with the mutant protein showed slowed activation currents that reached larger steady-state amplitudes compared to wildtype. The patients were ascertained through the GeneMatcher Program. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. (2020) identified a de novo heterozygous missense mutation in the CLCN6 gene (Y553C 602726.0001). (1997) identified 4 different CLCN6 cDNAs that represent alternatively spliced transcripts. By Northern blot analysis, Brandt and Jentsch (1995) found that CLCN6 was expressed as an approximately 6-kb mRNA in all tissues examined. Therefore, Brandt and Jentsch (1995) stated that CLCN6 and CLCN7 together define a new branch of the chloride channel protein family. The amino acid sequence of CLCN6 is 45% identical to that of CLCN7 ( 602727) but only 23 to 29% identical to the sequences of other known CLCNs. The predicted 869-amino acid protein was called CLC6 by them. (1994), Brandt and Jentsch (1995) cloned human cerebral cortex cDNAs that covered the entire CLCN6 coding region. Using the partial cDNA sequence of Nomura et al. Northern blot analysis revealed that CLCN6 was expressed widely. (1994) identified a partial human CLCN6 cDNA, which they called KIAA0046. Members of the mammalian CLCN family of voltage-gated chloride channels display differential tissue distribution and perform diverse functions.

Clc sequence viewer 6