In silico structure-function analysis of pathological variation in the HSD11B2 gene sequence.

Abstract:

:11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) is a short-chain dehydrogenase/reductase (SDR) responsible for inactivating cortisol and preventing its binding to the mineralocorticoid receptor (MR). Nonfunctional mutations in HSD11B2, the gene encoding 11betaHSD2, cause the hypertensive syndrome of apparent mineralocorticoid excess (AME). Like other such Mendelian disorders, AME is rare but has nevertheless helped to illuminate principles fundamental to the regulation of blood pressure. Furthermore, polymorphisms in HSD11B2 have been associated with salt sensitivity, a major risk factor for cardiovascular mortality. It is therefore highly likely that sequence variation in HSD11B2, having subtle functional ramifications, will affect blood pressure in the wider population. In this study, a three-dimensional homology model of 11betaHSD2 was created and used to hypothesize the functional consequences in terms of protein structure of published mutations in HSD11B2. This approach underscored the strong genotype-phenotype correlation of AME: severe forms of the disease, associated with little in vivo enzyme activity, arise from mutations occurring in invariant alignment positions. These were predicted to exert gross structural changes in the protein. In contrast, those mutations causing a mild clinical phenotype were in less conserved regions of the protein that were predicted to be relatively more tolerant to substitution. Finally, a number of pathogenic mutations are shown to be associated with regions predicted to participate in dimer formation, and in protein stabilization, which may therefore suggest molecular mechanisms of disease.

journal_name

Physiol Genomics

journal_title

Physiological genomics

authors

Manning JR,Bailey MA,Soares DC,Dunbar DR,Mullins JJ

doi

10.1152/physiolgenomics.00053.2010

subject

Has Abstract

pub_date

2010-08-01 00:00:00

pages

319-30

issue

3

eissn

1094-8341

issn

1531-2267

pii

physiolgenomics.00053.2010

journal_volume

42

pub_type

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