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A chimaeric llβ-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension

Abstract

GLUCOCORTICOID-REMEDIABLE Received 26 September; accepted 29 October 1991.aldosteronism (GRA), an autosomal dominant disorder, is characterized by hypertension with variable hyper aldosteronism1,2 and by high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxy-cortisol3–5, which are all under control of adrenocorticotropic hormone and suppressible by glucocorticoids6. 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 synthase7–9 and steroid 11β-hydroxylase7(expressed in both adrenal fasciculata and glomerulosa), which are 95% identical7 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 11β-hydroxylase to the coding sequences of aldosterone synthase (maximum lod score 5.23 for complete link-age, 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.

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Lifton, R., Dluhy, R., Powers, M. et al. A chimaeric llβ-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262–265 (1992). https://doi.org/10.1038/355262a0

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