APPARENT MINERALOCORTICOID EXCESS IN A BRAZILIAN KINDRED - HYPERTENSION IN THE HETEROZYGOTE STATE

Background Apparent mineralocorticoid excess (AME) is a cause of low-r enin, low-aldosterone hypertension in which cortisol acts as a mineral ocorticoid. The condition reflects an inability to inactivate cortisol to cortisone due to defective activity of the type 2 isozyme of 11 be ta-hydroxysteroid dehydrogenase (11 beta-HSD2). Homozygous mutations i n 11 beta-HSD2 gene in patients with AME have been described. A 7-year -old Brazilian girl had previously been found to have AME. Her father recently presented with mineralocorticoid hypertension at age 38 years . Objective To describe the clinical details, to perform steroid analy ses and to assess the molecular basis for the hypertension in this kin dred. Methods The 11 beta HSD2 gene was amplified from genomic DNA by the polymerase chain reaction and sequenced by direct chain-terminatio n sequencing on an automatic DNA sequencer. The sequencing results wer e validated by restriction-site polymorphism. The mutant 11 beta-HSD2 protein was expressed in Chinese hamster ovary polyoma cells and enzym atic activity was assessed by metabolizing cortisol in vitro. Results Sequence analysis of genomic DNA revealed a novel C1061T point mutatio n in exon V of the human 11 beta-HSD2 gene, resulting in an amino acid substitution of alanine by valine at codon 328 of the enzyme protein (A328V). Expression studies confirmed that the mutant protein was devo id of 11 beta-HSD2 activity. A Hhal restriction-site polymorphism conf irmed that the proband was homozygous for the mutation whereas both pa rents were heterozygotes. The father of the proband had hypertension, a normal serum potassium level, suppressed plasma renin activity and p lasma aldosterone level and a moderately elevated urinary cortisol : c ortisone metabolite ratio. Conclusions AME in this kindred is caused b y a novel mutation in the 11 beta-HSD2 gene. Detection of hypokalaemia , at least in this kindred, is an insensitive screening test for miner alocorticoid-based hypertension. In contrast to results from previousl y investigated kindreds, we have demonstrated that this kindred has an abnormal phenotype in the heterozygote state. Further studies are now required in order to evaluate the role of 11 beta-HSD2 activity in th e pathophysiology of `essential' hypertension.