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

Sartelet, A.; Stauber, T.; Coppieters, W.; Ludwig, C.F.; Fasquelle, C.; Druet, T.; Zhang, Z.; Ahariz, N.; Cambisano, N.; Jentsch, T.J.; Charlier, C.

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., Stauber, T., Coppieters, W., Ludwig, C.F., Fasquelle, C., Druet, T., Zhang, Z., Ahariz, N., Cambisano, N., 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
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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