Mechanistic Ancillary Study to the Natural History Study of ADO2 to Determine Clinical Severity

NIAMS增刊

Abstract NIAMS Supplement Abstract Autosomal dominant osteopetrosis type 2 (ADO2) is a rare disorder resulting from impaired osteoclastic bone resorption due to mutations in the Chloride Channel 7 gene, which cause disease by a dominant negative mechanism. Penetrance is approximately 66% and disease severity varies widely, even within the same family. Affected individuals typically have at least one significant clinical manifestation including fractures, osteonecrosis, osteomyelitis, blindness, or bone marrow failure. We previously demonstrated that osteoclasts cultured from monocytes of individuals with dominant osteopetrosis had markedly decreased pit resorption compared to osteoclasts isolated from carriers who had the same CLCN7 mutation. The osteoclasts from carriers actually resorbed bone similarly to those from control individuals. These studies demonstrated that osteoclast function, rather than the bone microenvironment, was responsible for the differences in bone between affected individuals and carriers. However, the mechanisms that determine influence disease penetrance and severity are unknown. This study will use a well-characterized cohort of subjects from an ongoing natural history study to study these mechanisms. Specifically, we will perform RNA-sequencing analysis using RNA isolated from osteoclasts from affected individuals, asymptomatic carriers and controls (without CLCN7 mutations) and determine differences in RNA expression to identify pathways/networks that differ between affected individuals, carriers and controls. Successful completion of the proposed aims will provide critical data revealing the pathways/networks determining whether an individual with a CLCN7 mutation clinically manifests with severe features or as a nonpenetrant carrier. In addition to providing important information about basic osteoclast biology, understanding the pathways/networks controlling penetrance and clinical severity will enable us to design targeted therapeutics for ADO2.