Abstract
CLC proteins comprise Cl− channels and anion/H+ antiporters involved in several fundamental physiological processes. ClC-7 is a lysosomal Cl−/H+ antiporter that together with its beta subunit Ostm1 has a critical role in the ionic homeostasis of lysosomes and of the osteoclasts’ resorption lacuna, although the specific underlying mechanism has so far remained elusive. Mutations in ClC-7 cause osteopetrosis, but also a form of lysosomal storage disease and neurodegeneration. Interestingly, both loss-of- and gain-of-function mutations of ClC-7 can be pathogenic, but the mechanistic implications of this finding are still unclear. This review will focus on the recent advances in our understanding of the biophysical properties of ClC-7 and of its role in human diseases with a focus on osteopetrosis and neurodegeneration.
Highlights
The two ClC-7 subunits are represented in grey and green, the two Ostm1 the membrane plane [6]
A detailed electrophysiological characterization recently showed that this mutant does mediate transport currents, their magnitude is strongly reduced compared to WT [41]. This finding potentially explains the phenotype of the E312A knock-in mouse model, as the residual current mediated by the E312A mutant could rescue the pigmentation phenotype and ameliorate the neurodegeneration compared to a full ClC-7 KO
Mutations in ClC-7 and Ostm1 can cause both ADO or Autosomal Recessive Osteopetrosis (ARO) [7,10], both characterized by a spectrum of phenotypic presentation that makes the classification quite difficult when no detailed genetic data are available for the affected families [52]
Summary
Human CLC proteins comprise Cl− channels and Cl− /H+ antiporters with fundamental roles in regulating electrical excitability, transepithelial transport and vesicular ionic homeostasis [1,2]. Mutations in ClC-7 and Ostm cause osteopetrosis [7,9,10], and a form of lysosomal storage disease and neurodegeneration [8,15,16], consistent with the phenotype of ClC-7 and Ostm loss-of-function mouse models [7,10]. Viewed from the the hClC-7/Ostm complex based on the work of Schrecker et al (PDB entry 7JM7) viewed from membrane plane [6]. The two ClC-7 subunits are represented in grey and green, the two Ostm the membrane plane [6].
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