title: A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension.
abstract: Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder, is characterized by hypertension with variable hyperaldosteronism and by high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, which are all under control of adrenocorticotropic hormone and suppressible by glucocorticoids. These abnormalities could result from ectopic expression of aldosterone synthase, which is normally expressed only in adrenal glomerulosa, in the adrenal fasciculata. Genes encoding aldosterone synthase and steroid 11 beta-hydroxylase (expressed in both adrenal fasciculata and glomerulosa), which are 95% identical and lie on chromosome 8q (refs 7, 10), are therefore candidate genes for GRA. Here we demonstrate complete linkage of GRA in a large kindred to a gene duplication arising from unequal crossing over, fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase (maximum lod score 5.23 for complete linkage, odds ratio of 170,000:1). This mutation can account for all the physiological abnormalities of GRA. Our result represents the demonstration of a mutation causing hypertension in otherwise phenotypically normal animals or humans.
authors.affiliation: Howard Hughes Medical Institute, University of Utah, Eccles Institute of Human Genetics, Salt Lake City, Utah 84132.
authors.forename: R P
authors.initials: RP
authors.lastname: Lifton
authors.forename: R G
authors.initials: RG
authors.lastname: Dluhy
authors.forename: M
authors.initials: M
authors.lastname: Powers
authors.forename: G M
authors.initials: GM
authors.lastname: Rich
authors.forename: S
authors.initials: S
authors.lastname: Cook
authors.forename: S
authors.initials: S
authors.lastname: Ulick
authors.forename: J M
authors.initials: JM
authors.lastname: Lalouel
mesh_terms: D001483:Base Sequence; D002678:Chimera; D003434:Crossing Over, Genetic; D019405:Cytochrome P-450 CYP11B2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism / Q000201:enzymology / Q000235:genetics*; D006973:Hypertension / Q000201:enzymology / Q000235:genetics*; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010375:Pedigree; D016133:Polymerase Chain Reaction; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D009838:Oligodeoxyribonucleotides; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase