CLINICAL & GENETIC STUDIES OF AUTOSOMAL DOMINANT OSTEOPETROSIS

2型常染色体显性遗传性骨质疏松症(ADO2)是一种由于破骨细胞介导的骨吸收失败而导致的遗传性疾病。虽然ADO2患者增加了骨密度，但骨骼质量较差，他们骨折的风险增加。这种疾病有75%的外显率，因此存在没有这种疾病典型放射学表现的“携带者”。然而，敏感的方法还没有被用来确定携带者是否在破骨细胞功能上有细微的缺陷。虽然ADO2是由于破骨细胞介导的骨吸收失败所致，但其发病机制尚不清楚，目前尚无该疾病的动物模型。本研究的目的是进一步描述该疾病的临床表现，并利用定位克隆技术确定导致该疾病的基因。为了实现我们的目标，我们将1)从ADO2家族成员那里获得用于生化和DNA研究的血液的表型特征；2)高分辨率地定位疾病基因；3)分离和克隆该基因。该基因的鉴定将有助于深入了解ADO2的病理生理机制，并有助于深入了解破骨细胞的调节和功能。

Type 2 autosomal dominant osteopetrosis (ADO2) is an inherited disorder that results from a failure in osteoclast mediated bone resorption. Although ADO2 patients have increased bone mineral density, the bone is of poor quality and they are at increased risk for fracture. The disease has a 75% penetrance, thus "carriers" exist that do not have the typical radiographic manifestations of the disorder. However, sensitive methods have not been used to determine if carriers have subtle defects in osteoclast function. Although ADO2 is due to a failure of osteoclast mediated bone resorption, the pathogenesis of the disorder is poorly understood and there are no animal models of the disorder. The goals of the present study are to further characterize the clinical manifestations of the disorder and to identify the gene responsible for the disorder using positional cloning techniques. To accomplish our goal we will 1) phenotypically characterize and obtain blood for biochemical and DNA studies from ADO2 family members; 2) map the disease gene with high resolution and 3) isolate and clone the gene. Identification of the gene will provide insight into the pathophysiology of ADO2 as well as provide insight into osteoclast regulation and function.