{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:27:18Z","timestamp":1791271638718,"version":"4.1.0"},"reference-count":51,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":3059,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Summary<\/jats:title><jats:p>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 perinatal 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.<\/jats:p>","DOI":"10.1242\/dmm.012500","type":"journal-article","created":{"date-parts":[[2013,10,24]],"date-time":"2013-10-24T02:35:29Z","timestamp":1382582129000},"source":"Crossref","is-referenced-by-count":25,"title":["A missense mutation accelerating the gating of the lysosomal Cl-\/H+-exchanger ClC-7\/Ostm1 causes osteopetrosis with gingival hamartomas in cattle"],"prefix":"10.1242","author":[{"given":"Arnaud","family":"Sartelet","sequence":"first","affiliation":[{"name":"University of Li\u00e8ge, Li\u00e8ge, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Stauber","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Centrum f\u00fcr Molekulare Medizin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"Coppieters","sequence":"additional","affiliation":[{"name":"University of Li\u00e8ge, Li\u00e8ge, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen F.","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Centrum f\u00fcr Molekulare Medizin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Fasquelle","sequence":"additional","affiliation":[{"name":"University of Li\u00e8ge, Li\u00e8ge, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Druet","sequence":"additional","affiliation":[{"name":"University of Li\u00e8ge, Li\u00e8ge, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Li\u00e8ge, Li\u00e8ge, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naima","family":"Ahariz","sequence":"additional","affiliation":[{"name":"University of Li\u00e8ge, Li\u00e8ge, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Cambisano","sequence":"additional","affiliation":[{"name":"University of Li\u00e8ge, Li\u00e8ge, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Jentsch","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Centrum f\u00fcr Molekulare Medizin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Charlier","sequence":"additional","affiliation":[{"name":"University of Li\u00e8ge, Li\u00e8ge, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2013,1,1]]},"reference":[{"key":"2021042513060048400_b1-0070119","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. 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