MOLECULAR-BASIS FOR HYPERTENSION IN THE TYPE-II VARIANT OF APPARENT MINERALOCORTICOID EXCESS

The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension in which cortisol acts as a potent mineralocorti coid. The type I variant results in a severe clinical and biochemical phenotype and arises because of mutations in the gene encoding the typ e 2 isozyme of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2), an enzyme responsible for the peripheral inactivation of cortisol to cor tisone. Only mild abnormalities of cortisol metabolism have been found in the type II variant of AME, suggesting that it may be a separate g ene defect. In an extensive consanguineous Sardinian pedigree affected with ''type II'' AME, a novel homozygous point mutation (C945T) was f ound in the human 11 beta-HSD2 gene in four affected individuals. Thir teen family members were heterozygous for the resultant R279C amino ac id substitution. The LOD score of linkage of the mutation to the disea se was 3.23. Expression of the 11 beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA. Affected individuals we re >30 years of age and had both mineralocorticoid hypertension and ev idence of impaired metabolism of cortisol to cortisone. The heterozygo te state was phenotypically normal but was associated with subtle defe cts in cortisol metabolism. AME represents a spectrum of mineralocorti coid hypertension with severity reflecting the underlying genetic defe ct in the 11 beta-HSD2 gene; classification into distinct subtypes is inappropriate. Hypertensive populations should be screened to identify the prevalence of milder defects in 11 beta-HSD2 in patients currentl y labeled as having ''essential'' hypertension.