title: A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle.
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 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.
authors.affiliation: Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, 4000-Liège (Sart Tilman), Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Sartelet
authors.forename: Tobias
authors.initials: T
authors.lastname: Stauber
authors.forename: Wouter
authors.initials: W
authors.lastname: Coppieters
authors.forename: Carmen F
authors.initials: CF
authors.lastname: Ludwig
authors.forename: Corinne
authors.initials: C
authors.lastname: Fasquelle
authors.forename: Tom
authors.initials: T
authors.lastname: Druet
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Naima
authors.initials: N
authors.lastname: Ahariz
authors.forename: Nadine
authors.initials: N
authors.lastname: Cambisano
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
authors.forename: Carole
authors.initials: C
authors.lastname: Charlier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D005882:Gingival Diseases / Q000150:complications / Q000235:genetics*; D006222:Hamartoma / Q000150:complications / Q000235:genetics*; D006239:Haplotypes; D006367:HeLa Cells; D006706:Homeostasis; D006720:Homozygote; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010022:Osteopetrosis / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels; D008565:Membrane Proteins; C489946:OSTM1 protein, human; D014443:Tyrosine; D044767:Ubiquitin-Protein Ligases
keywords: Belgian Blue cattle; CLCN7; Hamartomas; Ion homeostasis; Lysosomal storage; Osteopetrosis