MOLECULAR GENETICS OF LOW-RENIN HYPERTENSION

描述：（改编自申请人摘要）：Dr. Perrin白色 希望继续研究基因异常的作用， 编码醛固酮合成酶和11-羟基类固醇脱氢酶 活动在人类高血压的发展。 他此前曾 证明CYP 11B 1（类固醇11- 羟化酶）和CYP 11B 2（醛固酮合成酶）基因可以产生一种 具有醛固酮合酶活性的异常调节酶， 一种常染色体显性遗传性高血压， 糖皮质激素抑制性醛固酮增多症（GSH）。 他将试图 使用适当的临床， 生物化学和分子遗传学标准，并确定是否 可以在特定类型的突变之间建立相关性， 和疾病的临床表现，包括 高血压表型、高血压的严重程度、激素谱，以及 存在低钾血症。 他将检查一个频繁的（50%的每一个 两个等位基因）遗传多态性，可能会影响调节 CYP11B2。 它位于CYP 11B 2的5'调控区， 启动子结合关键基因的能力有4倍的差异 调节蛋白SF 1。白色医生将确定是否对应 两种形式的启动子的能力存在差异， 当合适的报告构建体被转录时， 转染到小鼠Y1肾上腺细胞或人肾上腺小球中 细胞，如果这两个等位基因的基因型与血液 正常和/或高血压个体的大群体中的血压。 他 将研究CYP 11B 2基因型与 其他基因的肾素-血管紧张素-醛固酮轴在决定 这些人群的血压。 据推测，11-羟基类固醇脱氢酶缺乏， 肾脏远端小管的活性导致常染色体 隐性高血压，称为表观盐皮质激素 过度 远端小管中酶的形式似乎是 与以前从肝脏克隆的酶不同，但可能是 与胎盘中表达的同工酶有关。 因此申请人 将分离编码人胎盘NAD+依赖性 形式的11-HSD，使用针对纯化的蛋白质的抗血清。 同时，他将分离编码11-HSD酶的cDNA克隆， 通过在爪蟾卵母细胞中表达而存在于兔远端小管中。 他 将表征对应于这些的人类基因组基因 酶，并在患有以下疾病的患者中寻找此类基因中的突变： 盐皮质激素明显过量如果发现这种突变， 确定基因中更频繁的多态性是否与 血压在正常人群中或在具有基本 高血压

DESCRIPTION: (Adapted from the applicant's abstract): Dr. Perrin White wishes to continue to investigate the role of abnormalities in the genes encoding aldosterone synthase and 11-hydroxysteroid dehydrogenase activities in the development of human hypertension. He has previously demonstrated that recombination between the CYP11B1 (steroid 11- hydroxylase) and CYP11B2 (aldosterone synthase) genes can generate an abnormally-regulated enzyme with aldosterone synthase activity, causing an autosomal dominant form of inherited hypertension termed glucocorticoid-suppressible hyperaldosteronism (GSH). He will attempt to identify family members with GSH using appropriate clinical, biochemical, and molecular genetic criteria and determine whether correlations can be established between the specific type of mutation and the clinical expression of the disease, including penetrance of the hypertensive phenotype, severity of hypertension, hormonal profile, and presence of hypokalemia. He will examine a frequent (50% for each of the two alleles) genetic polymorphism that may affect regulation of CYP11B2. It is located in the 5' regulatory region of CYP11B2, leading to a 4- fold difference in the ability of the promoter to bind a key regulatory protein, SF1. Dr. White will determine if corresponding differences exist in the abilities of the two forms of the promoter to direct transcription of appropriate reporter constructs when they are transfected into mouse Y1 adrenal cells or human adrenal glomerulosa cells, and if genotype for these two alleles is correlated with blood pressure in large groups of normal and/or hypertensive individuals. He will investigate possible correlations between genotype at CYP11B2 and other genes of the renin-angiotensin-aldosterone axis in determining blood pressure in these populations. It is hypothesized that a deficiency in 11-hydroxysteroid dehydrogenase activity in the distal tubule of the kidney leads to an autosomal recessive form of hypertension, termed apparent mineralocorticoid excess. The form of the enzyme in the distal tubule appears to be distinct from the enzyme previously cloned from the liver, but may be related to an isozyme expressed in placenta. Therefore, the applicant will isolate cDNA clones encoding the human placental, NAD+ dependent form of 11-HSD using an antiserum directed against the purified protein. In parallel, he will isolate cDNA clones encoding the 11-HSD enzyme(s) present in rabbit distal tubules by expression in Xenopus oocytes. He will characterize the human genomic gene(s) corresponding to these enzymes and search for mutations in such gene(s) in patients with apparent mineralocorticoid excess. If such mutations are found, he will determine if more frequent polymorphism in the gene correlates with blood pressure in a normal population or among individuals with essential hypertension.