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A missense mutation accelerating the gating of the lysosomal Cl(-)/H(+)-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle

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Item Type:Article
Title:A missense mutation accelerating the gating of the lysosomal Cl(-)/H(+)-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle
Creators Name:Sartelet, A. and Stauber, T. and Coppieters, W. and Ludwig, C.F. and Fasquelle, C. and Druet, T. and Zhang, Z. and Ahariz, N. and Cambisano, N. and Jentsch, T.J. and Charlier, C.
Abstract:Chloride/proton exchange by the lysosomal anion transporter ClC-7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal storage disease and mutations in either protein have been found to underlie osteopetrosis in mice and humans. Some human disease-causing CLCN7 mutations accelerate the usually slow voltage-dependent gating of ClC-7/Ostm1. However, it has remained unclear whether the fastened kinetics is indeed causative for the disease. Here we identified and characterized a new deleterious ClC-7 mutation in Belgian Blue Cattle with a severe symptomatology including peri-natal lethality and in most cases gingival hamartomas. By autozygosity mapping and genome-wide sequencing we found a handful of candidate variants, including a cluster of three private SNPs causing the substitution of a conserved tyrosine in the CBS2 domain of ClC-7 by glutamine. The case for ClC-7 was strengthened by subsequent examination of affected calves that revealed severe osteopetrosis. The Y750Q mutation largely preserved the lysosomal localization and assembly of ClC-7/Ostm1, but drastically accelerated its activation by membrane depolarization. These data provide first evidence that accelerated ClC-7/Ostm1 gating per se is deleterious, highlighting a physiological importance of the slow voltage-activation of ClC-7/Ostm1 in lysosomal function and bone resorption.
Keywords:CLCN7, Hamartomas, Osteopetrosis, Lysosomal Storage, Ion Homeostasis, Belgian Blue Cattle, Animals, Cattle, Mice
Source:Disease Models & Mechanisms
ISSN:1754-8403
Publisher:Company of Biologists (U.K.)
Volume:7
Number:1
Page Range:119-128
Date:January 2014
Official Publication:https://doi.org/10.1242/dmm.012500
PubMed:View item in PubMed

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