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

摘要NIAMS补充 摘要 常染色体显性遗传性石骨症2型（ADO2）是一种罕见的疾病，由于受损的骨皮质骨 由于氯离子通道7基因突变导致的吸收，其通过显性阴性引起疾病 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。 受影响的个体通常具有至少一种显著的临床表现，包括骨折， 骨坏死、骨髓炎、失明或骨髓衰竭。我们以前证明破骨细胞 从显性骨硬化症患者的单核细胞中培养的细胞， 与从具有相同CLCN 7突变的携带者中分离的破骨细胞相比。破骨细胞从 载体实际上与来自对照个体的那些类似地再吸收骨。这些研究表明 破骨细胞功能，而不是骨微环境，是造成骨差异的原因。 感染者和携带者之间的联系然而，决定影响疾病的机制 症状和严重程度未知。本研究将使用一个特征良好的受试者队列， 正在进行的自然史研究，以研究这些机制。具体来说，我们将进行RNA测序， 使用从受影响个体、无症状携带者和对照的破骨细胞分离的RNA进行分析 （没有CLCN 7突变），并确定RNA表达的差异，以鉴定 受影响的个体，携带者和对照之间存在差异。成功实现拟议目标将 提供关键数据，揭示确定CLCN 7个体是否 突变临床表现为严重特征或作为非渗透载体。除了提供 关于破骨细胞基本生物学的重要信息，了解控制 复发率和临床严重程度将使我们能够设计针对ADO2的靶向治疗方法。

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.