Abstract | BACKGROUND: OBJECTIVE: To describe the clinical details, to perform steroid analyses and to assess the molecular basis for the hypertension in this kindred. METHODS: The 11beta-HSD2 gene was amplified from genomic DNA by the polymerase chain reaction and sequenced by direct chain-termination sequencing on an automatic DNA sequencer. The sequencing results were validated by restriction-site polymorphism. The mutant 11beta-HSD2 protein was expressed in Chinese hamster ovary polyoma cells and enzymatic activity was assessed by metabolizing cortisol in vitro. RESULTS: Sequence analysis of genomic DNA revealed a novel C1061T point mutation in exon V of the human 11beta-HSD2 gene, resulting in an amino acid substitution of alanine by valine at codon 328 of the enzyme protein (A328V). Expression studies confirmed that the mutant protein was devoid of 11beta-HSD2 activity. A HhaI restriction-site polymorphism confirmed that the proband was homozygous for the mutation whereas both parents were heterozygotes. The father of the proband had hypertension, a normal serum potassium level, suppressed plasma renin activity and plasma aldosterone level and a moderately elevated urinary cortisol: cortisone metabolite ratio. CONCLUSIONS:
AME in this kindred is caused by a novel mutation in the 11beta-HSD2 gene. Detection of hypokalaemia, at least in this kindred, is an insensitive screening test for mineralocorticoid-based hypertension. In contrast to results from previously investigated kindreds, we have demonstrated that this kindred has an abnormal phenotype in the heterozygote state. Further studies are now required in order to evaluate the role of 11beta-HSD2 activity in the pathophysiology of ' essential' hypertension.
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Authors | A Li, K X Li, S Marui, Z S Krozowski, M C Batista, C B Whorwood, I J Arnhold, C H Shackleton, B B Mendonca, P M Stewart |
Journal | Journal of hypertension
(J Hypertens)
Vol. 15
Issue 12 Pt 1
Pg. 1397-402
(Dec 1997)
ISSN: 0263-6352 [Print] England |
PMID | 9431844
(Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Mineralocorticoids
- Hydroxysteroid Dehydrogenases
- 11-beta-Hydroxysteroid Dehydrogenases
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Topics |
- 11-beta-Hydroxysteroid Dehydrogenases
- Adult
- Animals
- Base Sequence
- Brazil
- Child
- Cricetinae
- Cricetulus
- Female
- Heterozygote
- Humans
- Hydroxysteroid Dehydrogenases
(genetics, metabolism)
- Hypertension
(genetics)
- Mineralocorticoids
(metabolism)
- Ovarian Neoplasms
(metabolism, pathology)
- Point Mutation
- Tumor Cells, Cultured
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