CLCN7 – Osteopetrosis

CLCN7 encodes the lysosomal chloride/proton antiporter ClC-7, essential for osteoclast-mediated bone resorption and lysosomal acidification. Pathogenic variants in CLCN7 lead to impaired chloride conductance and defective acidification of the resorption lacuna, manifesting clinically as osteopetrosis with variable neurologic and hematologic involvement. Loss-of-function and dominant-negative mutations in ClC-7 underlie autosomal recessive and autosomal dominant forms of osteopetrosis, respectively, while gain-of-function variants produce lysosomal storage and hypopigmentation without classic bone sclerosis.

Genetic Evidence

CLCN7-related osteopetrosis follows both autosomal recessive (ARO) and autosomal dominant (ADO) inheritance. In a consanguineous family, a novel homozygous c.1682G>A (p.Arg561Gln) variant segregated with classic malignant ARO across two affected siblings, confirmed by parental heterozygosity and autopsy findings in the second fetus (PMID:19238435). A large series of 94 early-onset osteopetrosis patients identified CLCN7 mutations in 12 cases, with seven harboring biallelic variants and five heterozygotes exhibiting intermediate phenotypes (PMID:14584882; PMID:12522560). Over 50 independent families and >150 probands worldwide have established a clear gene–disease correlation.

Variant Spectrum and Phenotype

Pathogenic CLCN7 alleles include missense substitutions (e.g., p.Arg561Gln, p.Arg526Gln), splice-site defects, and frameshifts. Homozygous or compound heterozygous loss-of-function variants cause severe infantile ARO, often with neurodegeneration, hematologic failure, and growth delay. Heterozygous dominant-negative mutations result in ADO type II, characterized by adult-onset bone sclerosis, fractures, and variable penetrance. Rare gain-of-function variants (e.g., p.Tyr715Cys) lead to lysosomal hyperacidity, organomegaly, and hypopigmentation without overt osteosclerosis.

Functional and Experimental Evidence

ClC-7 requires its β-subunit Ostm1 for stability and lysosomal targeting; Ostm1 deficiency reduces ClC-7 protein levels and phenocopies osteopetrosis (PMID:16525474). Electrophysiological assays in heterologous systems confirm 2Cl⁻/1H⁺ exchange activity, with disease-associated mutants showing trafficking defects (e.g., G215R) or altered gating kinetics (PMID:20830208). Cryo-EM structures of human ClC-7/Ostm1 reveal interfaces critical for slow voltage gating; mutations here disrupt antiporter function and lysosomal pH homeostasis (PMID:32851177). Mouse knockout models recapitulate osteopetrosis, neurodegeneration, and lysosomal storage, underscoring concordance between experimental systems and human disease.

Integration and Clinical Utility

The definitive association between CLCN7 and Osteopetrosis informs molecular diagnosis, prenatal testing, and therapeutic decisions such as hematopoietic stem cell transplantation. Genetic testing of CLCN7 should be prioritized in early-onset osteopetrosis, especially with neurologic features or a family history, and in ADO-II suspicion. Functional assays and structural insights enable variant classification and potential pharmacologic targeting of ClC-7 gating.

Key Take-home: CLCN7 mutation analysis is critical for accurate diagnosis and management of osteopetrosis, guiding genetic counseling, treatment planning, and evaluation of emerging targeted therapies.

References

• European Journal of Pediatrics • 2009 • A novel CLCN7 mutation resulting in a most severe form of autosomal recessive osteopetrosis. PMID:19238435
• Human Genetics • 2003 • Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis. PMID:12522560
• Nature • 2006 • ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. PMID:16525474
• 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
• Science Advances • 2020 • Molecular insights into the human CLC-7/Ostm1 transporter. PMID:32851177

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