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

摘要NIAMS补编 摘要 常染色体显性遗传性骨化症2型(ADO2)是一种罕见的疾病，由破骨细胞性骨损伤引起。 由氯离子通道7基因突变引起的吸收，该基因通过显性阴性导致疾病 机制。外显率约为66%，疾病严重程度差异很大，即使在同一个家庭中也是如此。 受影响的人通常至少有一种重要的临床表现，包括骨折， 骨坏死、骨髓炎、失明或骨髓衰竭。我们之前证明了破骨细胞 从显性骨化症患者的单核细胞培养出来的细胞显著减少了凹陷吸收 与从具有相同CLCN7突变的携带者中分离的破骨细胞进行比较。其中的破骨细胞 携带者实际上吸收了与对照组相似的骨骼。这些研究表明， 破骨细胞功能，而不是骨骼微环境，是造成骨骼差异的原因。 在受影响的个人和携带者之间。然而，决定疾病的机制会影响疾病 穿透力和严重程度尚不清楚。这项研究将使用一组具有良好特征的受试者 正在进行的自然历史研究，以研究这些机制。具体来说，我们将执行RNA测序 用从患者、无症状携带者和对照中提取的破骨细胞RNA进行分析 (没有CLCN7突变)，并确定RNA表达的差异，以确定 在受影响的个人、携带者和对照之间存在差异。成功完成拟议的目标将 提供关键数据，揭示决定是否患有CLCN7的个体的途径/网络 突变具有严重的临床特征或表现为非穿透性携带者。除了提供 关于基本破骨细胞生物学的重要信息，了解控制的途径/网络 外显性和临床严重性将使我们能够设计针对ADO2的靶向疗法。

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.