Polymorphisms of the CLCN7 Gene Are Associated With BMD in Women

We show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 in the CLCN7 gene is associated with femoral neck BMD in women

Ulrika Pettersson


Scholarcy highlights

  • The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD
  • Heterozygous missense mutations in the CLCN7 gene have been found to cause a milder form of osteopetrosis termed autosomal dominant osteopetrosis type II and to account for a few cases of so called “intermediate” osteopetrosis where the disease severity is between that of recessive osteopetrosis and ADO II. The physiological function of the chloride channel 7, encoded by the CLCN7 gene remained obscure until Kornak showed that disruption of CLCN7 in mice led to severe osteopetrosis because of a failure of osteoclasts to secrete acid and to resorb bone. ClC-7 plays an essential role for acidification of the extracellular resorption lacunae, which is crucial for osteoclast-mediated resorption of mineralized bone
  • The CLCN7 gene on chromosome 16p13.3 encodes ClC7, which belongs to the chloride channel family of voltage-gated ion channels. These channels have 10–16 transmembrane domains as well as 2 cystosolic domains and form homodimers with two identical pores. ClC-7 is highly expressed in the osteoclast ruffled border and is thought to provide the chloride conductance required for efficient proton pumping in the ruffled membrane and participates in the secretion of acid into the resorption lacunae, which is necessary for dissolving mineralized bone. The importance of ClC-7 in bone metabolism became obvious when disruption of the CLCN7 gene in mice resulted in severe osteopetrosis because of a failure of the osteoclasts to secrete acid and resorb bone. Mutations of the CLCN7 gene have been shown to be responsible for other forms of osteopetrosis
  • We observed a significant association between polymorphisms in exon 15 of CLCN7 and femoral neck BMD, and both of these polymorphisms were in strong linkage disequilibrium with each other and on multiple regression analysis, one of these polymorphisms rs12926669 was found to be an independent predictor of FN-BMD accounting for ∼1% of the variance of bone mass at this site in our population
  • Both exon 15 single nucleotide polymorphism were associated with BMD, it seems likely that the rs12926669 polymorphism may have been responsible for driving the association that was observed, because this is a nonsynonymous coding polymorphism that results in an amino acid change from of valine to methionine at codon 418
  • The V418M polymorphism is located in the eighth transmembrane domain, which is a highly conserved region of the channel. the specific residue is not conserved across species, because the CLCN7 gene in rats contains a methionine at codon 418.(25) The function of the different transmembrane domains still remains obscure and many of the known mutations in ADOII and autosomal recessive osteopetrosis cluster in the conserved CBS2 domain, which is thought to be involved in protein sorting. others lie within the conserved transmembrane domains D2–D4, which have been proposed to influence the channel’s functional properties. The function of D8, still remains largely unknown and further studies will be required to determine if the V418M amino acid change has functional consequences
  • Our study suggests that a subtle polymorphic variation within exon 15 of the CLCN7 gene contributes to the genetic regulation of FN BMD in Scottish women and adds to the accumulating body of evidence that suggests that subtle polymorphisms in genes that cause monogenic bone diseases contribute to the genetic regulation of BMD in the normal population

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