The effects of disease-causing ClC-7 mutations on lysosomal pH.

Abstract

Lysosomes are highly acidic organelles that degrade worn-out or surplus cell elements into smaller, reusable components. This acidic environment is generated by the V-ATPase, which promotes lysosomal function. However, other proteins are needed to create a counterion pathway that offsets an increasing membrane potential. The chloride/proton antiporter ClC-7 is one protein that has been linked to controlling lysosomal pH through counterion transport. Dysregulation of ClC-7 in humans can cause osteopetrosis, neurodegeneration, and lysosomal storage disease. We recently reported two patients with a CLC-7 gain-of-function mutation, Y715C, which causes hypopigmentation and lysosomal storage disease. Cells from these patients contain hyperacidic lysosomes, and heterologous expression of ClC-7 with the Y715C mutation resulted in greatly increased ClC-7 transport activity. These findings are consistent with ClC-7 playing a role in setting lysosomal pH. Here, we report three new patients with novel ClC-7 mutations and comparable but less severe disease symptoms. We explore the effects of these three mutations on ClC-7 function and lysosomal pH.