In silico structure-function analysis of pathological variation in the HSD11B2 gene sequence
- 1 August 2010
- journal article
- research article
- Published by American Physiological Society in Physiological Genomics
- Vol. 42 (3), 319-330
- https://doi.org/10.1152/physiolgenomics.00053.2010
Abstract
11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) 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 11βHSD2, 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 11βHSD2 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.Keywords
This publication has 70 references indexed in Scilit:
- The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiativeChemico-Biological Interactions, 2009
- Protein structure prediction on the Web: a case study using the Phyre serverNature Protocols, 2009
- Jalview Version 2—a multiple sequence alignment editor and analysis workbenchBioinformatics, 2009
- Ensembl 2009Nucleic Acids Research, 2008
- The Jpred 3 secondary structure prediction serverNucleic Acids Research, 2008
- Statistical potential for assessment and prediction of protein structuresProtein Science, 2006
- The Protein Data BankNucleic Acids Research, 2000
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993
- Assessment of protein models with three-dimensional profilesNature, 1992
- Basic local alignment search toolJournal of Molecular Biology, 1990