Identification of TCIRG1 and CLCN7 gene mutations in a patient with autosomal recessive osteopetrosis.

Osteopetrosis is a heritable bone disorder that exhibits highly clinical and genetical heterogeneity, and is caused by defective osteoclastic resorption. The three main forms are the autosomal recessive severe (ARO), the intermediate autosomal and the autosomal dominant benign osteopetrosis forms. In the present study, the clinical, biochemical and radiological manifestations were described in a patient with osteopetrosis. Sequence analysis identified the compound heterozygous mutations, c.909C>A (p.Tyr303X) and c.2008C>T (p.Arg670X), in TCIRG1, and a heterozygous splicing mutation, c.1798-1G>T, in the chloride channel 7 gene (CLCN7). Two aberrant forms of the CLCN7 transcripts, c.1798_1883 (exon 20) deletion predicted to cause p.Leu601GlyfsX13, and the c.1798_1821 deletion, the first 24 bp of the exon 20, predicted to cause p.Gly600_Gln607del, were detected by further analysis of the splicing patterns in the leukocytes. The patient's asymptomatic mother carried the TCIRG1 c.909C>A (p.Tyr303X) and CLCN7 c.1798-1G>T mutations, while the asymptomatic father carried the TCIRG1 c.2008C>T (p.Arg670X) mutation only. The patient was finally diagnosed with ARO on the basis of clinical and biochemical parameters, radiological changes and genetic defects. To the best of our knowledge, this is the first reported case of a patient with osteopetrosis who carries TCIRG1 and CLCN7 mutations. In addition, among the three mutations, TCIRG1 c.909C>A and CLCN7 c.1798-1G>T were novel mutations.