GENETICS, BARTTER'S, GITELMAN'S AND PHA-II

产品说明：（改编自申请人的摘要）在上一个资助期，这些工作人员已经确定了四种遗传性盐耗形式的分子基础，包括低钾血症和血压降低：Gitelman综合征。Bartter综合征I型、II型和III型。此外，他们还绘制了两个基因，导致孟德尔形式的高血压假性醛固酮减少症II型。他们已经收集了大量患有这些疾病的患者，在目前的项目中，他们将研究这些疾病的基因和表型。特异性目标1将确定Gitelman综合征和Bartter综合征患者中这些基因的突变谱。这些研究将表征这些蛋白质的功能结构域，还将鉴定可用于通过个体激酶追踪疾病等位基因的家族中的特定突变。这些研究还将允许比较这些基因中不同基因突变引起的临床表型。此外，他们将确定不存在突变的激酶，为确定新的血压改变基因提供机会。最后，这些研究将为调查遗传0、1或2个突变基因拷贝的指示病例的大家族提供临床基础。初步结果表明，这些基因对血压，钙稳态和骨密度的影响。此外，临床研究将确定纯合子遗传对体内平衡、骨密度和利尿剂反应的影响。使用与已知基因无关的家族，他们还将进行连锁分析，试图识别导致这些表型的新基因。最后，他们将继续进行PHAII基因的定位克隆。

DESCRIPTION: (Adapted from the applicant's abstract) In the previous funding period, these workers have identified the molecular basis of four inherited forms of salt wasting with hypokalemic alkalosis and diminished blood pressure: Gitelman's syndrome,. Bartter's syndromes type I, type II and type III. In addition, they have mapped tow genes causing the Mendelian form of hypertension pseudohypoaldosteronism type II. They have collected a very large cohort of patients with these disease and in the current project will investigate the genes and phenotypes in these diseases. Specific Aim 1 will determine the spectrum of mutations in these genes in patients with Gitelman's and Bartter's syndromes. These studies will characterize functional domains of these proteins and will also identify specific mutations in families that can be used to track disease alleles through individual kindreds. These studies will also permit comparison of clinical phenotypes arising from mutations in different of these genes. Moreover, they will identify kindreds in whom no mutation is present, providing opportunity to identify new blood pressure-altering genes. Finally, these studies will provide clinical substrate for investigation of extended families of index cases who inherit 0, 1 or 2 copies of mutant genes. Preliminary results demonstrate effects of these genes on blood pressure, calcium homeostasis and bone density. Furthermore clinical studies will determine the impact of inheritance of homozygous of homeostasis, bone density and response to diuretics. Using families that are unlinked to known genes, they will also perform analysis of linkage to attempt to identify new genes causing these phenotypes. Finally, they will pursue the positional cloning of the genes for PHAII.