Glucocorticoid-suppressible hyperaldosteronism: effects of crossover site and parental origin of chimaeric 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.
Jamieson
A
A
Department of Medicine and Therapeutics, Western Infirmary, Glasgow, U.K.
Slutsker
L
L
Inglis
G C
GC
Fraser
R
R
White
P C
PC
Connell
J M
JM
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002678:Chimera; D003434:Crossing Over, Genetic; D019405:Cytochrome P-450 CYP11B2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D006929:Hyperaldosteronism / Q000188:drug therapy / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics
D005938:Glucocorticoids; D003577:Cytochrome P-450 Enzyme System; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase