GLUCOCORTICOID-SUPPRESSIBLE HYPERALDOSTERONISM - EFFECTS OF CROSSOVER SITE AND PARENTAL ORIGIN OF CHIMERIC GENE ON PHENOTYPIC-EXPRESSION

1. Genetic analysis of five kindreds with glucocorticoid-suppressible hyperaldosteronism, four of whom had not been subjected to any previous genetic analysis, revealed three different crossover breakpoints within the five kindreds clustered in the exon 3-intron 4 region of the chimaeric gene, The site of the crossover point had no effect on blood pressure within the kindreds studied. 2. The gene causing glucocorticoid-suppressible hyperaldosteronism was in strong linkage disequilibrium with an allele of a newly described restriction enzyme polymorphism of the aldosterone synthase gene promoter region, suggesting a possible role for this allele in the development of the chimaeric gene. 3. A novel observation on subjects inheriting glucocorticoid-suppressible hyperaldosteronism from their mothers showed that they had significantly higher plasma aldosterone concentrations and mean arterial blood pressures than those inheriting glucocorticoid-suppressible hyperaldosteronism from their fathers. 4. These results raise the possibility that chronic exposure in utero to elevated plasma aldosterone concentrations may result in the permanent programming of mineralocorticoid-dependent blood pressure regulatory mechanisms, which is amplified in later life by the elevated plasma aldosterone concentrations found in glucocorticoid-suppressible hyperaldosteronism.