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.
| Zhang, Junhui; Geller, David S (2008) Helix 3-helix 5 interactions in steroid hormone receptor function. J Steroid Biochem Mol Biol 109:279-85 |
| Mani, Arya; Radhakrishnan, Jayaram; Wang, He et al. (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278-82 |
| Alvarez de la Rosa, Diego; Gimenez, Ignacio; Forbush, Biff et al. (2006) SGK1 activates Na+-K+-ATPase in amphibian renal epithelial cells. Am J Physiol Cell Physiol 290:C492-8 |
| Zhang, Junhui; Tsai, Francis T F; Geller, David S (2006) Differential interaction of RU486 with the progesterone and glucocorticoid receptors. J Mol Endocrinol 37:163-73 |
| Zhang, Junhui; Simisky, Jessica; Tsai, Francis T F et al. (2005) A critical role of helix 3-helix 5 interaction in steroid hormone receptor function. Proc Natl Acad Sci U S A 102:2707-12 |
| Geller, David S (2005) Mineralocorticoid resistance. Clin Endocrinol (Oxf) 62:513-20 |
| Wilson, Frederick H; Hariri, Ali; Farhi, Anita et al. (2004) A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science 306:1190-4 |
| Coric, Tatjana; Hernandez, Nelmary; Alvarez de la Rosa, Diego et al. (2004) Expression of ENaC and serum- and glucocorticoid-induced kinase 1 in the rat intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 286:G663-70 |
| Geller, David S (2004) A genetic predisposition to hypertension? Hypertension 44:27-8 |
| Francis, Jean; Zhang, Junhui; Farhi, Anita et al. (2004) A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant 19:2893-5 |
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