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

Jonathan Manning, Matthew A. Bailey, Dinesh C. Soares, Donald R. Dunbar, John J. Mullins

Research output: Contribution to journalArticlepeer-review


Manning JR, Bailey MA, Soares DC, Dunbar DR, Mullins JJ. In silico structure-function analysis of pathological variation in the HSD11B2 gene sequence. Physiol Genomics 42: 319-330, 2010. First published June 22, 2010; doi: 10.1152/physiolgenomics.00053.2010.-11 beta -Hydroxysteroid dehydrogenase type 2 (11 beta HSD2) is a shortchain dehydrogenase/reductase (SDR) responsible for inactivating cortisol and preventing its binding to the mineralocorticoid receptor (MR). Nonfunctional mutations in HSD11B2, the gene encoding 11 beta HSD2, 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 11 beta HSD2 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.

Original languageEnglish
Pages (from-to)319-330
Number of pages12
JournalPhysiological Genomics
Issue number3
Publication statusPublished - Aug 2010


  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • Amino Acid Sequence
  • Animals
  • Computational Biology
  • DNA Mutational Analysis
  • Databases, Genetic
  • Family
  • Genetic Predisposition to Disease
  • Humans
  • Hypertension
  • Mineralocorticoid Excess Syndrome, Apparent
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins
  • Polymorphism, Genetic
  • Protein Conformation
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship


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