A genetic defect resulting in mild low-renin hypertension.
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.
Pediatric Endocrinology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA.
R C
RC
Wilson
S
S
Dave-Sharma
J Q
JQ
Wei
V R
VR
Obeyesekere
K
K
Li
P
P
Ferrari
Z S
ZS
Krozowski
C H
CH
Shackleton
L
L
Bradlow
T
T
Wiens
M I
MI
New
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D003348:Cortisone / Q000378:metabolism; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D008901:Mineralocorticoids / Q000378:metabolism*; D010375:Pedigree; D017354:Point Mutation; D012083:Renin / Q000172:deficiency*
D017931:DNA Primers; D008901:Mineralocorticoids; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D012083:Renin; D003348:Cortisone; D006854:Hydrocortisone