BES2003 Poster Presentations Steroids (39 abstracts)
Mutations in the HSD11B2 gene causing AME in the Oman population
AJ Atterbury 1 , N Draper 1 , GG Lavery 1 , EA Walker 1 , V DeSilva 2 , NF Taylor 3 , S Hala 4 , N Rajendra 4 , B Bappal 4 & PM Stewart 1
1Department of Medicine, University of Birmingham, Birmingham, UK; 2Department of Chemical Pathology, Royal Hospital, Oman; 3Kings College Hospital, London, UK; 4Department of Child Health, Royal Hospital, Oman.
Mutations in the HSD11B2 gene explain the syndrome of apparent mineralocorticoid excess (AME), which is characterised by severe hypokalaemic hypertension. Cortisol acts as a mineralocorticoid through failure of its inactivation to cortisone by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). Patients are diagnosed by a raised THF+allo-THF/THE ratio. To date, approximately 30 mutations have been described in HSD11B2. Recently, three apparently unrelated kindreds with AME have been referred to us from Oman.
In the affected cases, age at onset was <1yr, urinary THF+allo-THF/THE ratios ranged between 3.66-17, blood pressure ranged between 127/72-169/101 and Na/K ratios ranged between 134/1.35-139/4.2.
Mutation analysis of the HSD11B2 gene was performed. Genomic DNA was extracted and the five coding exons, including intron/exon boundaries, were PCR amplified and subjected to direct DNA sequencing. In kindred 1, homozygosity for a 6 nucleotide deletion in exon 2 was detected. The mutation, L114del6nt, causes the loss of Leu114 and Glu115 form the 11beta-HSD2 enzyme, and a previous report showed that these residues were crucial for cofactor binding and therefore result in attenuated enzyme activity. In kindred 2, homozygosity for a novel C441T substitution was detected in exon 3. This generates the missense mutation A221V in the amino acid sequence. We speculate that pre-mRNA splicing fidelity may be compromised as the mutation lies 2 base pairs form the intron 3 donor splice site and therefore requires functional analysis. In kindred 3, homozygosity for a novel 9-nucleotide insertion was discovered in exon 5. This mutation, V322ins9nt, maintains the correct reading frame while inserting 3 additional codons encoding, alanine, proline and valine.
The molecular defects in three kindreds with AME are defined. These additional mutations provide further insight into AME and the function of the 11beta-HSD2 enzyme. Finally, AME may be a prevalent cause of hypertension in certain ethnic groups, such as the Oman population.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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