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

遗传学、BARTTERs、GITELMANs 和 PHA-II

• 批准号: 6844651
• 负责人: RICHARD P LIFTON
• 金额: $ 23.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844651
• 关键词: Bartter' s syndrome; Xenopus oocyte; autosomal dominant trait; clinical research; electrolyte balance; family genetics; gene mutation; genetic mapping; genetic markers; genotype; human genetic material tag; human population genetics; human subject; hypoaldosteronism; hypotension; inborn biological transport disorder; inborn renal tubular transport disorder; linkage mapping; molecular genetics; phenotype; renal tubular transport; single strand conformation polymorphism

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.

描述：（改编自申请人的摘要）在之前的资助期间，这些工作人员已经确定了四种遗传性盐消耗形式的分子基础，伴有低钾性碱中毒和血压降低：Gitelman 综合征。 Bartter 综合征 I 型、II 型和 III 型。此外，他们还绘制了导致 II 型高血压假性醛固酮增多症孟德尔形式的两种基因图谱。他们收集了大量患有这些疾病的患者，在当前的项目中将研究这些疾病的基因和表型。具体目标 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域，还将鉴定家族中的特定突变，这些突变可用于通过个体亲属追踪疾病等位基因。这些研究还将允许比较由不同这些基因的突变引起的临床表型。此外，他们将识别出不存在突变的亲属，从而提供识别新的血压改变基因的机会。最后，这些研究将为研究继承 0、1 或 2 个突变基因拷贝的指示病例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。利用与已知基因无关的家族，他们还将进行连锁分析，以尝试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。