CLCN7 – Autosomal Recessive Osteopetrosis

CLCN7 encodes the lysosomal chloride/proton exchanger ClC-7, which is essential for osteoclast-mediated bone resorption and lysosomal acidification. Pathogenic biallelic CLCN7 variants cause autosomal recessive osteopetrosis (ARO), characterized by increased bone density, bone marrow failure, and multisystem involvement. ARO patients often present in infancy with classical radiological hallmarks, hematological cytopenias, organomegaly, and variable neurodegeneration.

Genetic evidence for CLCN7 involvement in ARO includes multiple unrelated probands harboring compound heterozygous or homozygous CLCN7 variants under an autosomal recessive inheritance model. Four infantile cases have been described: a Chinese patient with c.285+1G>A and p.Ala299Val (PMID:26477479), a Pakistani family with homozygous p.Ser204Trp (PMID:29926385), a neonatal case with p.Arg526Trp (PMID:35515972), and two Chinese siblings with novel and canonical CLCN7 variants (PMID:34545712). These four probands establish robust genetic support under recessive inheritance.

The variant spectrum includes splice-donor mutations (e.g., c.285+1G>A), missense variants affecting conserved residues (e.g., p.Ser204Trp, p.Arg526Trp, p.Lys519Phe, p.Leu342Pro) and deep intronic changes causing pseudoexon inclusion. No recurrent founder allele has been identified. Segregation analysis in all pedigrees confirmed trans inheritance from heterozygous parents without additional affected relatives.

Functional studies demonstrate that CLCN7 variants impair ClC-7 activity and osteoclast function. Splice-site and deep-intronic mutations abolish normal transcript processing; missense variants reduce chloride currents or disrupt lysosomal localization in heterologous systems and patient-derived cells. hiPSC-derived osteoclasts from an ARO patient with p.Gly292Glu and p.Arg403Gln show absent bone resorption, consistent with loss of function. Clcn7–/– mice recapitulate osteopetrosis and neurodegeneration, confirming concordant mechanistic insights.

No studies dispute the CLCN7–ARO association; phenotypic variability reflects modifier effects and the differential impact of specific variants on ClC-7 gating or stability. While gain-of-function CLCN7 variants cause distinct lysosomal storage and hypopigmentation syndromes without osteopetrosis, all recessive CLCN7-ARO alleles reported lead to loss of function.

In summary, biallelic loss-of-function CLCN7 variants underlie autosomal recessive osteopetrosis with consistent genetic and experimental corroboration. CLCN7 genetic testing should be integrated into diagnostic workflows for infantile osteopetrosis, and functional assays of novel variants guide clinical interpretation.

Key Take-home: CLCN7 loss-of-function variants cause ARO via impaired ClC-7–mediated lysosomal acidification and osteoclast resorption, supporting molecular diagnosis and potential targeted therapies.

References

• Gene • 2016 • A novel mutation and a known mutation in the CLCN7 gene associated with relatively stable infantile malignant osteopetrosis in a Chinese patient. PMID:26477479
• Molecular biology reports • 2018 • Whole exome sequencing identified two novel homozygous missense variants in the same codon of CLCN7 underlying autosomal recessive infantile malignant osteopetrosis in a Pakistani family. PMID:29926385
• Sisli Etfal Hastanesi tip bulteni • 2022 • A Neonatal Case of Infantile Malignant Osteopetrosis Presenting with Thrombocytopenia and Hypotonicity: A Novel Mutation in Chloride Voltage-Gated Channel 7 Gene. PMID:35515972
• Molecular genetics & genomic medicine • 2021 • Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis. PMID:34545712

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