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.
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