A point mutation in CLCN6 has been identified as the genetic cause of a severe, lysosomal neurodegenerative disorder. Researchers from Germany, Italy and the United States detected the identical de novo missense variant of CLCN6 in three unrelated children with a severe phenotype of developmental delay, generalized hypotonia, respiratory insufficiency and neurodegenerative symptoms. ClC-6, the encoded protein, belongs to the CLC family of voltage-gated chloride channel proteins, which allow the exchange of negatively charged chloride ions between the cell and its environment and are relevant in various cellular processes including acidification of intracellular vesicles.

The scientists revealed by functional analysis that the mutation in CLCN6 leads to a gain of function of ClC-6. This ion transporter is predominantly found on late endosomes, which fuse with lysosomes. These cell organelles are responsible for enzymatic degradation of extracellular material as well as intracellular proteins that are no longer needed by the cell. Disturbances of the endolysosomal system are often associated with neurodegenerative disorders since neurons, which no longer proliferate, particularly depend on the elimination of accumulations from the cell. The study published in the American Journal of Human Genetics shows that hyperactivation of ClC-6 causes an increased transport of chloride and protons into the affected cells, leading to lysosomal dysfunction.