TY - JOUR AU - ZHANG Xiao-ya AU - HE Jin-wei AU - FU Wen-zhen AU - WANG Chun AU - ZHANG Zhen-lin PY - 2017 TI - Novel mutations of TCIRG1 cause a malignant and mild phenotype of autosomal recessive osteopetrosis (ARO) in four Chinese families JF - Acta Pharmacologica Sinica; Vol 38, No 11 (November 2017): Acta Pharmacologica Sinica Y2 - 2017 KW - N2 - 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-yearold 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. UR - http://www.chinaphar.com/article/view/9675