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

描述：（改编自申请人的摘要）在之前的资助期内，这些工作人员已经确定了四种遗传形式的盐消耗与低钾性碱中毒和血压降低的分子基础：吉特尔曼综合征，。Bartter综合征，I型，II型和III型。此外，他们还绘制了导致孟德尔型高血压假性醛固酮减少症II型的两个基因图谱。他们已经收集了一大批患有这些疾病的患者，在目前的项目中，他们将调查这些疾病的基因和表型。Specific Aim 1将确定Gitelman综合征和Bartter综合征患者这些基因的突变谱。这些研究将表征这些蛋白质的功能域，并将确定家庭中的特定突变，这些突变可用于通过单个种类跟踪疾病等位基因。这些研究还将允许比较由不同这些基因突变引起的临床表型。此外，他们将识别没有突变的种类，为识别新的改变血压的基因提供机会。最后，这些研究将为研究遗传0、1或2个突变基因拷贝的索引病例的大家庭提供临床基础。初步结果表明，这些基因对血压、钙稳态和骨密度有影响。此外，临床研究将确定遗传纯合子对体内平衡、骨密度和利尿剂反应的影响。利用与已知基因没有联系的家族，他们还将进行联系分析，试图识别导致这些表型的新基因。最后，他们将进行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.