TWO X-LINKED GENES THAT REGULATE MINERAL HOMEOSTASIS

描述（改编自申请人的摘要）：本申请的原始目标是： 研究是为了确定两个基因在人类中的生理作用， X染色体对矿物质平衡有重要控制作用。临床研究 映射到两个感兴趣基因座的遗传性疾病患者表明， 一种基因是甲状旁腺胚胎发生所必需的（从而 维持细胞外液钙水平），以及其他基因控制 血磷浓度和维生素D在肾脏的生物活化 水平具体来说，遗传缺陷导致X连锁隐性特发性 甲状旁腺功能减退（XHPT）和X连锁低磷血症（XLH）。XHPT基因座 已经缩小到一个独特的1.5 Mb区域，大型亲属和三个 候选基因已被鉴定。参与XLH的基因被称为PEX或 PHEX（X染色体上的磷酸调节内肽酶），但调节 它的表达和编码蛋白的功能还不清楚。 PEX似乎能降解一种称为磷酸激素的磷酸尿激素。在 根据过去的评价意见，这一两次修订的申请， 忽略了XLH调查。对于XHPT，本提案的具体目标侧重于 候选基因的分离和鉴定， 精确的致病突变（和相应的基因），以及 XHPT基因的生物学作用的表征。

DESCRIPTION (Adapted from the Applicant's Abstract): The original goal of this research was to define the physiological roles of two genes on the human X-chromosome that importantly control mineral homeostasis. Clinical studies of patients with heritable disorders mapped to the two loci of interest show that one gene is essential for embryogenesis of the parathyroid glands (and thereby maintenance of extracellular fluid calcium levels), and the other gene controls blood phosphate concentrations and the bioactivation of vitamin D at the kidney level. Specifically, the genetic defects cause X-linked recessive idiopathic hypoparathyroidism (XHPT) and X-linked hypophosphatemia (XLH). The XHPT locus has been narrowed to a 1.5 Mb region in a unique, large kindred and three candidate genes have been identified. The gene involved in XLH is called PEX or PHEX (phosphate-regulating endopeptidase on the X-chromosome), but regulation of its expression and the function of the encoded protein are not understood. PEX seems to degrade a phosphaturic hormone designated phosphatonin. In response to past evaluation comments, this twice amended application has omitted XLH investigations. For XHPT, the Specific Aims of this proposal focus on isolation and characterization of candidate genes, identification of the precise causative mutation (and corresponding gene), and initiation of characterization of the biological role of the XHPT gene.