TWO X-LINKED GENES THAT REGULATE MINERAL HOMEOSTASIS

调节矿物质稳态的两个 X 连锁基因

• 批准号: 2655144
• 负责人: MICHAEL P WHYTE
• 金额: $ 20.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-12 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2655144
• 关键词: artificial chromosomes; clinical research; family genetics; genetic mapping; human genetic material tag; human subject; hypoparathyroidism; inborn metabolism disorder; molecular cloning; nucleic acid sequence; phosphorus metabolism disorders; sex chromosomes

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.

目标是识别、克隆、测序和表征两个基因 控制儿童矿物质稳态的人类 X 染色体。 尽管编码蛋白质的功能仍有待确定， 我们对患有与两个基因座相关的缺陷的患者进行的临床研究 兴趣表明，其中之一对于甲状旁腺的发育至关重要，并且 另一个控制磷酸盐稳态。 具体而言，缺陷导致 X连锁隐性特发性甲状旁腺功能减退症（HPT）和X连锁 低磷血症（HYP）。 我们已经绘制了受影响地区的疾病位点图 家庭，包括当地人口的独特资源，以及 相应的基因存在于重叠的 YAC 克隆中 手。 该提案的具体目标首先集中于隔离 这两种疾病的候选基因来自它们所在的 YAC 本地化。 将使用多种协议，包括新的重组- 基于在与 cDNA 序列同源的位点截断 YAC 的方法， 基于CpG靶向测序的候选基因推断 包含基因座的基因组 DNA 岛和长链。 继 分离候选基因后，研究将转向鉴定 真正的候选者，并伴随对突变变化的分析 受影响的个人。 这些研究将作为一条途径 将基因型变化与疾病的严重程度和病理生理学相关联 疾病，并作为蛋白质产品和特性表征的前奏 基因修饰或破坏的影响。