Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADOII) and intermediate autosomal recessive osteopetrosis (ARO) in seven Chinese families

Defects in the chloride channel 7 (CLCN7) gene lead to autosomal dominant osteopetrosis type II (ADOII, OPTA2 MIM 166600) and autosomal recessive osteopetrosis, autosomal recessive 4 (ARO, OPTB4 MIM 611490). The objective of the present study was to expand the mutational spectrum and analyze the correlation between mutational sites and clinical phenotypes.Seven affected individuals from unrelated Chinese families were clinically examined. X-ray examination and biochemical markers were evaluated. The 25 exons of CLCN7 and exon-intron boundaries were amplified and analyzed; we also used μ-CT to distinguish the features of sclerotic bone from the great trochanter of Pt 6 using the bones of unaffected subject in vitro.We identified six cases of OPTA2 and one case of OPTB4. One OPTA2 patient displaying life-threatening symptoms died, and the OPTB4 patient presenting a relatively mild clinical course survived. We identified eight different CLCN7 mutations, including three novel mutations (p.G240E, p.F318S, and p.S753W), and μ-CT analysis showed that the volumetric bone mineral density, total porosity and open porosity of sclerotic bone were higher than the control.The present study revealed three novel mutations, showed the dense but brittle sclerotic bones of an OPTA2 patient, characterized OPTA2 symptoms from benign to fatal and reported a rare intermediate case of ARO in a Chinese population.