Abstract
Human autosomal recessive osteopetrosis (ARO), also known as infantile malignant osteopetrosis, is a rare genetic bone disorder that often causes death. Mutations in T-cell immune regulator 1 (TCIRG1) are a frequent cause of human ARO. Six additional genes (TNFSF11, TNFRSF11A, CLCN7, OSTM1, SNX10, PLEKHM1) were also found to be associated with human ARO. In order to expand the mutation spectrum and clinical diversity for a better understanding of the ARO phenotype and to further investigate the clinical characteristics of benign subjects with ARO, we here report five individuals with ARO from four unrelated Chinese families. X-ray examination was conducted and bone turnover markers were assayed. The gene of T-cell immune regulator 1 (TCIRG1) was screened and analyzed. Monocyte-induced osteoclasts were prepared and their resorption ability was studied in vitro. We identified five novel mutations (c.66delC, c.1020+1_1020+5dup, c.2181C>A, c.2236+6T>G, c.692delA) in these patients. Four patients displayed a malignant phenotype, three of them died, and one who received bone marrow transplantation survived. The remaining one, a 24-year-old male from a consanguineous family, was diagnosed based on radiological findings but presented no neurological or hematological defects. He was homozygous for c.2236+6T>G in intron 18; this mutation influenced the splicing process. An in vitro functional study of this novel splicing defect showed no resorption pits on dentine slices. TCIRG1-dependent osteopetrosis with a mild clinical course was observed for the first time in Chinese population. The present findings add to the wide range of phenotypes of Chinese patients with TCIRG1-dependent ARO and enrich the database of TCIRG1 mutations.
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Acknowledgements
We thank all patients and family members who participated in this study.
This work is supported by grants from the National Basic Research Program of China (973 Program, 2014CB942903), National Natural Science Foundation of China (NSFC, 81370978, 8127096), The Science and Technology Commission of Shanghai Municipality (14JC1405000), and the Science and Technology Commission of Chongqing Municipality (CSTC2013jcyjC00009). Special thanks should be given to Guo-ying ZHU from the Institute of Radiation Medicine, Fudan University for cell culture guidance.
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Supplementary information is available at the website of Acta Pharmacologica Sinica.
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Supplementary Table S1
Primer sequences of TCIRG1 (DOC 33 kb)
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Zhang, Xy., He, Jw., Fu, Wz. et al. Novel mutations of TCIRG1 cause a malignant and mild phenotype of autosomal recessive osteopetrosis (ARO) in four Chinese families. Acta Pharmacol Sin 38, 1456–1465 (2017). https://doi.org/10.1038/aps.2017.108
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DOI: https://doi.org/10.1038/aps.2017.108
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