Figure 317

Genetics of glucocorticoid-remediable aldosteronism (GRA): schematic representation of unequal crossover in GRA. The genes for aldosterone synthase (Aldo S) and 11 ß-hydroxylase (11 ß-OHase) are normally expressed in separate zones of the adrenal cortex. Aldosterone is produced in the zona glomerulosa and cortisol, in the zona fasciculata. These enzymes have identical intron-extron structures and are closely linked on chromosome 8. If unequal crossover occurs, a new hybrid gene is produced that includes the 5' segment of the 11 P-OHase gene (ACTH-response element and the 11 p-OHase segment) plus the 3' segment of the Aldo S gene (aldosterone synthase segment). The chimeric gene is now under the contol of ACTH, and aldosterone secretion is enhanced, thus causing hypokalemia and hypertension. By inhibiting pituitary release of ACTH, glucocorticoid administration leads to a fall in aldosterone levels and correction of the clinical and biochemical abnormalities of GRA. The presence of Aldo S activity in the zona fasciculata gives rise to characteristic elevations in 18-oxidation products of cortisol (18-hydroxycortisol and 18-oxocortisol), which are diagnostic for GRA [8].

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