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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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