CLCN7; hamartomas; osteopetrosis; lysosomal storage; ion homeostasis; Belgian Blue Cattle
Abstract :
[en] 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.
Research Center/Unit :
Giga-Genetics - ULiège
Disciplines :
Veterinary medicine & animal health Biochemistry, biophysics & molecular biology Genetics & genetic processes
Author, co-author :
Sartelet, Arnaud ✱; Université de Liège - ULiège > Département de production animales > GIGA-R: Génomique animale
Ahariz, Naïma ; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
Cambisano, Nadine ; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
Jentsch, Thomas J.; FMP (Leibniz-Institut fuer Molekulare Pharmakologie) and MDC (Max-Delbrueck-Centrum fuer Molekulare Medizin) > Robert-Roessle-Strasse, 10 > 13125 BERLIN - GERMANY
Charlier, Carole ; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
✱ These authors have contributed equally to this work.
Language :
English
Title :
A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle.
Publication date :
January 2014
Journal title :
Disease Models and Mechanisms
ISSN :
1754-8411
eISSN :
1754-8403
Publisher :
Company of Biologists, Cambridge, United Kingdom
Volume :
7
Pages :
119-128
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
Rilouke! Tares et Pathologies à Composante Héréditaire en Race Blanc-Bleu Belge, Vers le Développement d’un Réseau Intégré de Lutte Je164/7 and SFB740
Funders :
DGA - Région wallonne. Direction générale de l'Agriculture ULiège - Université de Liège F.R.S.-FNRS - Fonds de la Recherche Scientifique BELSPO - SPP Politique scientifique - Service Public Fédéral de Programmation Politique scientifique DFG - Deutsche Forschungsgemeinschaft
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