Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase

• Published in: Nature genetics Vol. 2; no. 1; pp. 66 - 74
• Main Authors: Lifton, Richard P, Dluhy, Robert G, Powers, Michael, Rich, Glenn M, Gutkin, Michael, Fallo, Francesco, Gill, John R, Feld, Leonard, Ganguly, Arunabha, Laidlaw, Jack C, Murnaghan, D.J, Kaufman, Chris, Stockigt, Jan R, Ulick, Stanley, Lalouel, Jean-Marc
• Format: Journal Article
• Language: English
• Published: United States 01.09.1992
• Subjects: aldosterone synthase; Alleles; Base Sequence; Chimera - genetics; chimeras; Crossing Over, Genetic; Cytochrome P-450 CYP11B2; Cytochrome P-450 Enzyme System - genetics; DNA - genetics; duplication; Female; Gene Expression; genes; glucocorticoid-remediable aldosteronism; Haplotypes - genetics; Humans; hypertension; Hypertension - genetics; Linkage Disequilibrium; Male; man; Molecular Sequence Data; Multigene Family; Pedigree; Steroid 11-beta-Hydroxylase - genetics; Steroid Hydroxylases - genetics
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng0992-66

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.