TWO X-LINKED GENES THAT REGULATE MINERAL HOMEOSTASIS

目标是识别、克隆、测序和表征两个基因 控制儿童体内矿物质平衡的人类X染色体。 虽然编码蛋白的功能仍有待确定， 我们对两个基因座连锁缺陷患者的临床研究 研究表明，甲状旁腺激素对甲状旁腺发育和 另一种是控制磷酸盐的动态平衡。具体地说，缺陷导致 X连锁隐性特发性甲状旁腺功能减退症 低磷(HYP)。我们已经绘制了受影响地区的疾病地点图 家庭，包括当地人口中独特的资源，以及 在重叠的YAC克隆中存在相应的基因 手。 该提案的具体目标首先集中在隔离 这两种疾病的候选基因来自于他们所在的YAC 本地化。将使用几种协议，包括一种新的重组- 基于在与cDNA序列同源的位置截断YAC的方法， 基于CpG靶向测序的候选基因推断 含有这些基因座的岛屿和长长的基因组DNA。紧随其后的是 分离候选基因，研究将转向鉴定 真正的候选者，以及对基因突变的分析 受影响的个体。这些研究既是一种途径，也是一种 本病的严重程度和病理生理学与基因改变的相关性 疾病，并作为表征蛋白质产品和 基因修改或破坏的影响。

The goal is to identify, clone, sequence, and characterize two genes on the human X chromosome that control mineral homeostasis in children. Although the function of the encoded proteins remains to be determined, our clinical studies of patients with defects linked to the two loci of interest show that one is essential for parathyroid gland development and the other controls phosphate homeostasis. Specifically, the defects cause X-linked recessive idiopathic hypoparathyroidism (HPT) and X-linked hypophosphatenia (HYP). We have mapped the disease loci in affected families, including unique resources in local populations, and the corresponding genes are present in overlapping YAC clones that are on hand. The specific aims of the proposal focus first on the isolation of candidate genes for the two diseases from YACs in which they are localized. Several protocols will be used, including a new recombination- based method that truncates a YAC at sites homologous to cDNA sequences, and inference of candidate genes based on targeted sequencing of CpG islands and long tracts of genomic DNA harboring the loci. Following the isolation of candidate genes, studies would turn to identification of the true candidates, with accompanying analysis of the mutational changes in affected individuals. These studies would serve both as a route to correlate genotypic changes with the severity and pathophysiology of the disease, and as a prelude to characterization of the protein products and the effects of gene modification or disruption.