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.

Dental and Cranial Pathologies in Mice Lacking the Cl−/H+‐Exchanger ClC‐7

“…In many cases of osteopetrotic animals and human patients, the absence of teeth, or severe delay in tooth eruption, is a characteristic feature and often the first sign of osteopetrosis (Van Wesenbeeck and Van Hul, 2005). Osteopetrotic cattle with a Clcn7 mutation display gross gingival hamartomas, also likely linked to non-erupting teeth (Sartelet et al, 2014). Abnormal tooth eruption has been attributed to the deficiency of osteoclasts and subsequent defect in alveolar bone resorption during tooth development (Van Wesenbeeck and Van Hul, 2005).…”

Approach to Investigating Congenital Skeletal Abnormalities in Livestock

“…In a recent investigation of gingival hamartomas in Belgian blue cattle, it was not until a mutation was found in a gene associated with osteopetrosis that the bones were examined and found to be osteopetrotic. 93 Although skeletal abnormalities of nutritional or toxic origin tend to be variable in presentation, inherited skeletal defects are typically more consistent. An exception to this paradigm is chondrodysplasia of Texel sheep (Fig.…”

Genetics of the neuronal ceroid lipofuscinoses (Batten disease)

“…For example, CLCN7 underlies the severe autosomal recessive disease infantile malignant osteopetrosis, and when the osteopetrosis is treated with bone marrow transplantation, patients go on to develop blindness and CNS degeneration, suggesting that specific mutations or alleles in this gene may cause NCL-like disease. Intriguingly, recent evidence in cattle indicates that mutations in CLCN7 also underlie severe gingival hamartomas and osteopetrosis, with evidence suggesting NCL-like lysosomal storage is present in these animals [26]. …”