Identification of the CLCN7 gene mutations in two Chinese families with autosomal dominant osteopetrosis (type II)

Here we report the identification of two different mutations in chloride channel 7 gene in two unrelated patients with autosomal dominant osteopetrosis type II. We determined that one patient (a 32-year-old woman) carried a heterozygous gene for a R767W mutation in exon 24, and another patient (a 17-year-old boy) carried a heterozygous gene for a novel frameshift mutation (Glu798FS) in exon 25. Recent studies have reported loss-of-function mutations in the chloride channel 7 (CLCN7) gene as a cause of autosomal dominant osteopetrosis type II (ADO-II). The identification of gene mutations in Chinese with ADO has not been reported previously. In this study, we identified mutations of the CLCN7 gene in two unrelated Chinese families with ADO-II. Two probands with ADO-II were diagnosed based on their bone characteristics on X-rays and their laboratory results. All 25 exons of the CLCN7 gene, including the exon–intron boundaries, were sequenced. We found in family 1 that the proband (a 32-year-old woman) was heterozygous for a CLCN7 mutation. The nonsynonymous mutation consisted of a heterozygous C/T transition at codon 2327 in exon 24, which resulted in an arginine (CGG)-to tryptophan (TGG) substitution at position 767 (R767W). The same heterozygous mutation (C/T) was determined in her father and son, who were asymptomatic with normal skeleton radiography. In family 2, we found that the proband (a 17-year-old boy) carried a novel frameshift mutation (Glu798FS) resulting from a G insertion between codon 60 and codon 61 in exon 25. The heterozygous –/G insertion is predicted to elongate the peptide of CLCN7 by 120 amino acids after position 797 amino acids. Similarly, some individuals of this family carried the same heterozygous mutation, but they are all asymptomatic. Furthermore, the R767W and Glu798FS mutations were not found in 100 unrelated controls. Our present findings suggest that the novel Glu798FS mutation in exon 25 and R767W in exon 24 in the CLCN7 gene were responsible for ADO-II in these Chinese patients.