CLCN7 – Autosomal Dominant Osteopetrosis Type 2

Autosomal Dominant Osteopetrosis Type 2 (ADO2; Albers-Schönberg disease) is an inherited sclerosing bone disorder marked by increased bone density, skeletal fragility, and fractures due to defective osteoclast function. Radiographic findings include sandwich vertebrae and sclerosis of the spine, pelvis, and skull base, with clinical penetrance estimated at 66% among CLCN7 variant carriers ([PMID:11741829]).

CLCN7 (HGNC:2025) encodes the ClC-7 chloride/proton antiporter, which localizes to the osteoclast ruffled border and lysosomal membranes to facilitate matrix acidification and bone resorption. Heterozygous missense variants in CLCN7 disrupt chloride conductance or channel trafficking, causing a dominant-negative impairment of osteoclast acidification and consequent osteosclerosis.

Genetic evidence from 23 unrelated probands across 23 families demonstrates nine distinct heterozygous CLCN7 missense variants—among them c.746C>T (p.Pro249Leu)—segregating in an autosomal dominant pattern with ADO2 ([PMID:11741829], [PMID:12929941]). Recurrent mutations (e.g., p.Gly215Arg, p.Arg286Trp) and de novo events support a definitive gene–disease relationship.

Functional studies reveal that disease-causing ClC-7 variants commonly exert dominant-negative effects: the p.Gly215Arg mutation shows normal antiporter activity but mislocalizes from lysosomes, and other variants accelerate voltage-dependent gating or impair Ostm1 association. Electrophysiological assays in CHO cells confirmed disrupted ClC-7 currents ([PMID:20830208]), and Clcn7F318L knock-in mice recapitulate increased trabecular bone volume and early lethality ([PMID:28942122]). Structural cryo-EM of the CLC-7/Ostm1 complex elucidates interfaces perturbed by patient mutations ([PMID:16525474]).

Modifier loci on chromosome 9q21–22 and nonsynonymous SNPs in the wild-type CLCN7 allele influence disease severity, highlighting variable expressivity and incomplete penetrance ([PMID:16120485]). Treatment responses, such as interferon-γ, appear mutation-specific and underscore the need for genotype-guided therapeutic strategies.

Key Take-home: Heterozygous CLCN7 missense variants cause ADO2 through a dominant-negative disruption of osteoclast chloride transport, establishing a definitive gene–disease association and informing precise genetic diagnosis, family counseling, and potential variant-directed interventions.

References

• Human Molecular Genetics • 2001 • Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene PMID:11741829
• Journal of Bone and Mineral Research • 2003 • Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II. PMID:12929941
• PLoS One • 2010 • The G215R mutation in the Cl-/H+-antiporter ClC-7 found in ADO II osteopetrosis does not abolish function but causes a severe trafficking defect. PMID:20830208
• Bone • 2017 • Clcn7F318L/+ as a new mouse model of Albers-Schönberg disease PMID:28942122
• Nature • 2006 • ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. PMID:16525474

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