Apparent mineralocorticoid excess: genotype is correlated with biochemical phenotype

The syndrome of apparent mineralocorticoid excess is a form of hypertension inherited in an autosomal recessive manner. This disorder results from mutations in the HSD11K (HSD11B2) gene, which encodes the kidney isozyme of 11beta-hydroxysteroid dehydrogenase. This enzyme converts active glucocorticoids such as cortisol and corticosterone to their inactive metabolites cortisone and 11-dehydrocorticosterone. An elevated ratio of cortisol to cortisone metabolites in the urine (tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone [(THF+aTHF)/THE]) is considered pathognomic for this disorder. To determine whether the biochemical phenotype of this disorder is correlated with genotype, we expressed enzymes carrying each of the six known missense mutations in cultured cells. Only one mutant, R337C, had detectable activity in cell lysates, but five of six mutants were partially active in whole cells. Apparent kinetic constants for cortisol and corticosterone were determined in whole cells, and the apparent first-order rate constant, Vmax/Km, was used as a measure of enzymatic activity. The urinary (THF+aTHF)/THE ratio in patients carrying each mutation was strongly correlated with in vitro enzymatic activity of the corresponding mutant (r=.839, P=.001 with cortisol as the substrate). We conclude that the biochemical phenotype of the syndrome of apparent mineralocorticoid excess is largely determined by genotype.