Functional and biochemical analyses show that, in addition to altered voltage-dependent gating property and reduced Cl− current amplitude, leukodystrophy-causing ClC-2 mutant channels are associated with defective protein stability and impaired membrane trafficking [11,13,20], consistent with the presence of disease-related anomalous ClC-2 protein homeostasis (proteostasis). Here, CLCN2 is linked to leukodystrophy.