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

ABSTRACT

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

KEYWORDS:

• Osteopetrosis
• CLCN7
• ADOII
• ARO
• μ-CT

Acknowledgments

The authors thank the patients and family members who participated in the present study.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was financially supported through grants from the National Basic Research Program of China [973 Program, 2014CB942903], the National Natural Science Foundation of China [NSFC81370978, 81170803, and 8127096], the Science and Technology Commission of Shanghai Municipality [14JC1405000], the Shanghai Municipal Commission of Health and Family Planning [20164Y0062], and the Shanghai Jiao Tong University Affiliated Sixth People’s Hospital grant [Grant 1644].