Analysis of the 11βHydroxysteroid Dehydrogenase T

Authors: Mariniello Barbara Ronconi Vanessa Sardu Cipriana Pagliericcio Antonella Galletti Ferruccio Strazzullo Pasquale Palermo Mario Boscaro Marco Stewart Paul M Mantero Franco Giacchetti Gilberta

Publish Date: 2005/08/01

Volume: 18, Issue: 8, Pages: 1091-1098

PDF Link

Abstract

Barbara Mariniello Vanessa Ronconi Cipriana Sardu Antonella Pagliericcio Ferruccio Galletti Pasquale Strazzullo Mario Palermo Marco Boscaro Paul M Stewart Franco Mantero Gilberta Giacchetti Analysis of the 11βHydroxysteroid Dehydrogenase Type 2 Gene HSD11B2 in Human Essential Hypertension American Journal of Hypertension Volume 18 Issue 8 August 2005 Pages 1091–1098 https//doiorg/101016/jamjhyper200502020The HSD11B2 gene encoding the kidney isoenzyme 11βhydroxysteroid dehydrogenase is a candidate for essential hypertension We previously showed that the frequency of shorter alleles of a CA repeat polymorphism in the first intron of 11βHSD2 gene was significantly higher among saltsensitive than saltresistant individuals with hypertensionExons 2 3 4 and 5 were screened by polymerase chain reaction–singlestrand conformation polymorphism analysis in 292 hypertensive patients and 163 control subjects The samples with variant electrophoretic patterns at singlestrand conformation polymorphism were reanalyzed using an automated DNA sequencer A casecontrol study was then performed by comparing genotype frequencies in hypertensive and normotensive subjectsAnalysis of the HSD11B2 showed that in hypertensive patients there is a higher prevalence of two associated polymorphisms Thr156/ThrC468A in exon 2 ex2 and Glu178/GluG534A in exon 3 ex3 than in normotensive subjects 9 v 24 This association did not correlate with salt sensitivity C468A alone correlates significantly with hypertension 9 and was identified only in 3 of control subjects P 05 whereas G534A was identified also in about 7 of normotensive subjects The urinary free cortisol/urinary free cortisone ratio UFF/UFE was significantly higher in hypertensive patients compared with control subjects P 01Two different polymorphisms of the HSD11B2 gene were observed The association of both polymorphisms was significantly higher in hypertensive subjects than in control subjects Its role should be further investigated but it could be related to other mutations in the promoter region of HSD11B2 or to the modulation of 11βHSD2 mRNA processing in hypertensive subjects Am J Hypertens 2005181091–1098 © 2005 American Journal of Hypertension LtdThe enzyme 11βhydroxysteroid dehydrogenase 11βHSD is responsible for the interconversion of cortisol–cortisone in human beings Two isoforms of the enzyme have been identified 11βHSD types 1 and 2 The first catalyzes both 11βdehydrogenation and the reverse 11oxoreduction reactions and it is expressed predominantly in glucocorticoid target tissues liver testis lung adipose pituitary12 The 11βHSD2 isoform binds NAD with high affinity and catalyzes only 11βdehydrogenation3 This isoform is critical for mineralocorticoid receptor specificity and is predominantly expressed in mineralocorticoid target tissues kidney colon salivary glands and in fetal tissues including the placenta45 The HSD11B2 gene is 62 kb long localized to chromosome 16q22 and contains 5 exons6Mutations in the HSD11B2 gene cause the syndrome of apparent mineralocorticoid excess AME characterized by severe hypertension hypokalemia and low plasma renin activity78 In this condition absence of 11βHSD2 prevents conversion of cortisol into cortisone resulting in a rise in intracellular cortisol levels overstimulation of the mineralocorticoid receptor MR and cortisolinduced mineralocorticoid excess910 The AME syndrome arises because of mutations in HSD11B2 inherited as an autosomal recessive trait Both homozygous11 and compound heterozygous mutations have been reported12 Principally in exons 3 to 5 the gene mutations been detected which significantly impair 11βHSD2 enzymatic activityA second variant of AME the socalled AME type II13 is characterized by a milder phenotype with onset in late adolescence or early adulthood and by a less deranged cortisol metabolism compared with the classical disease Nevertheless these patients also have mutations within the HSD11B2 gene and a classification of this syndrome into distinct variants is inappropriate The AME syndrome should be considered a continuum disorder in which defects of HSD11B2 gene encoding mutant cDNA result in varying degrees of enzymatic impairment

Keywords: