Abstract
Autosomal dominant osteopetrosis type II (ADO II), characterized by increased bone mass and density, is caused by mutations in the chloride channel 7 (CLCN7) gene. In this study, a novel missense variant in CLCN7 (c.1678A > G; p.Met560Val) was identified in three symptomatic subjects and one carrier of a Chinese family with ADO II. Notably, bone formation markers, including osteocalcin and total procollagen type N-terminal propeptide, have increased or presented at the upper limit of the normal range in the three patients. Serum factors secreted by osteoclast lineage cells and affecting the CD31hiEMCNhi vessel formation, such as tartrate-resistant acid phosphatase 5b, platelet-derived growth factor-BB, vascular endothelial growth factor, and SLIT3, had a higher expression in three ADO II subjects than in 15 healthy age-matched and sex-matched controls. Moreover, the conditioned medium was obtained from preosteoclast induced from the ADO II patients’ peripheral blood mononuclear cells. It was found to promote the CD31hiEMCNhi vessel formation of human microvascular endothelial cells and osteogenic differentiation of bone marrow-derived stem cells. Taken together, our finding revealed a novel CLCN7 variant associated with ADO II and suggested that the sclerotic bone was potentially associated with the increase of the CD31hiEMCNhi vessel formation and bone formation.
Highlights
Autosomal dominant osteopetrosis type II (ADO II; OPTA2, Online Mendelian Inheritance in Man: 166600), known as “Albers Schönberg disease,” is the most common type of osteopetrosis with an estimated prevalence of 2.5/100,000 (Bénichou et al, 2000; Del Fattore et al, 2008)
The common complications are confined to the skeleton, including bone fracture, bone pain, osteomyelitis, and rare bone marrow failure (Bénichou et al, 2000)
Genetic and molecular diagnoses were available for patients with ADO II, especially to the missense mutations in the chloride channel 7 (CLCN7) gene (Bollerslev et al, 2013)
Summary
Autosomal dominant osteopetrosis type II (ADO II; OPTA2, Online Mendelian Inheritance in Man: 166600), known as “Albers Schönberg disease,” is the most common type of osteopetrosis with an estimated prevalence of 2.5/100,000 (Bénichou et al, 2000; Del Fattore et al, 2008). It is characterized by segmentary osteosclerosis, predominantly involving in the vertebral endplates (“rugger-jersey spine”), iliac wings (“bone within bone” sign), and the skull base. CLCN7 (Online Mendelian Inheritance in Man: 602727) is a multi-pass membrane protein that acts as a Cl-/H + exchanger by voltage gate (Leisle et al, 2011) It mainly resides in the late endosomes, lysosomes, and the ruffled membrane of osteoclasts. Recent research demonstrated that the specific small interfering RNA therapy normalized extra-skeletal manifestations on the ADO II mouse (Maurizi et al, 2019)
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