A genetic defect resulting in mild low-renin hypertension

Abstract

Severe low-renin hypertension has few known causes. Apparent mineralocorticoid excess (AME) is a genetic disorder that results in severe juvenile low-renin hypertension, hyporeninemia, hypoaldosteronemia, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. In 1995, it was shown that mutations in the gene (HSD11B2) encoding the 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2) cause AME. Typical patients with AME have defective 11beta-HSD2 activity, as evidenced by an abnormal ratio of cortisol to cortisone metabolites and by an exceedingly diminished ability to convert [11-3H]cortisol to cortisone. Recently, we have studied an unusual patient with mild low-renin hypertension and a homozygous mutation in the HSD11B2 gene. The patient came from an inbred Mennonite family, and though the mutation identified her as a patient with AME, she did not demonstrate the typical features of AME. Biochemical analysis in this patient revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared with 0-6% in typical patients with AME whereas the normal conversion is 90-95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous C-->T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L). The parents and sibs were heterozygous for this mutation. In vitro expression studies showed an increase in the Km (300 nM) over normal (54 nM). Because approximately 40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene.

Figure 1

Pedigree of Mennonite family showing consanguinity (50).

Figure 2

Mutations in the gene for 11β-hydroxysteroid dehydrogenase type 2 in patients with AME. These patients were investigated by our group, and the phenotypes are well described. The HSD11B2 gene has five exons, is 6.2 kb long, and has been mapped to chromosome 16q22. The mutation in Patient 15 is reported here (identified by an arrow). All mutations found in affected patients are homozygous except for Patient 3, who is a compound heterozygote.

Figure 3

Determination of K_m value (Michaelis–Menten constant) for the metabolism of cortisol by 11β-HSD2 enzyme in CHOP cell homogenates transfected with pP227L in the presence of 20% glycerol (transfection with pHSD2 resulted in a K_m of 54 nM).

Figure 4

Western blot analysis of homogenates from CHOP cells transfected with pP227L, wild type (pHSD2) or pcDNA1 vector.

Figure 5

Calculation of the frequency of a mild form of AME among an inbred Mennonite population of 2,000 members. This calculation would be a minimum frequency if no additional patients with AME are found.