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A genetic defect resulting in mild low-renin hypertension
R C Wilson1, S Dave-Sharma, J Q Wei
1Pediatric Endocrinology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA.
Summary
Genetic analysis of the HSD11B2 gene is suggested for patients with low-renin hypertension. A novel mutation in this gene can cause mild hypertension without typical apparent mineralocorticoid excess symptoms.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Apparent mineralocorticoid excess (AME) is a severe genetic disorder causing juvenile low-renin hypertension, linked to mutations in the HSD11B2 gene.
- The 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) enzyme, encoded by HSD11B2, is crucial for inactivating cortisol.
- Defective 11beta-HSD2 activity leads to mineralocorticoid receptor overstimulation, causing hypertension.
Observation:
- A patient from an inbred family presented with mild low-renin hypertension and a homozygous HSD11B2 mutation.
- Despite the mutation, the patient lacked typical severe AME features.
- Biochemical analysis revealed a moderately elevated cortisol/cortisone metabolite ratio and reduced cortisol-to-cortisone conversion (58% vs. 0-6% in typical AME).
Findings:
- A novel homozygous C-->T mutation at codon 227 (P227L) in the HSD11B2 gene was identified.
- In vitro studies showed this mutation increased the enzyme's Km, indicating reduced efficiency.
- Heterozygous parents and siblings carried the mutation, suggesting familial inheritance.
Implications:
- This finding expands the phenotypic spectrum of HSD11B2 mutations.
- Genetic testing of HSD11B2 may be beneficial for individuals with low-renin hypertension, a condition seen in ~40% of essential hypertension cases.
- Understanding HSD11B2 variants can improve diagnosis and management of hypertension subtypes.