CLN7 is an organellar chloride channel regulating lysosomal function

Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive lysosomal storage diseases. One variant form of late-infantile NCL (vLINCL) is caused by mutations of a lysosomal membrane protein CLN7, the function of which has remained unknown. Here, we identified CLN7 as a novel endolysosomal chloride channel. Overexpression of CLN7 increases endolysosomal chloride currents and enlarges endolysosomes through a Ca2+/calmodulin-dependent way. Human CLN7 and its yeast homolog exhibit characteristics of chloride channels and are sensitive to chloride channel blockers. Moreover, CLN7 regulates lysosomal chloride conductance, luminal pH, and lysosomal membrane potential and promotes the release of lysosomal Ca2+ through transient receptor potential mucolipin 1 (TRPML1). Knocking out CLN7 causes pathological features that are similar to those of patients with vLINCL, including retinal degeneration and autofluorescent lipofuscin. The pathogenic mutations in CLN7 lead to a decrease in chloride permeability, suggesting that reconstitution of lysosomal Cl- homeostasis may be an effective strategy for the treatment of vLINCL.

Automated summary

NCLs are a group of lysosomal storage diseases caused by autosomal recessive mutations. One variant of NCL, vLINCL, is caused by mutations in the lysosomal membrane protein CLN7, which has been identified as a novel endolysosomal chloride channel. Overexpression of CLN7 can increase chloride currents and enlarge endolysosomes, suggesting a potential treatment strategy for vLINCL.