A new compound heterozygous mutation in the 11β-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess

Abstract

Apparent mineralocorticoid excess (AME) characterized by early-onset hypertension and hypokalemia is due to congenital deficiency of 11β- hydroxysteroid dehydrogenase (11βHSD). Two isoforms of human 11βHSD are known, and the type 2 isoform (11βHSD2) has been recently shown to be responsible for AME. In this study we have analyzed the 11βHSD2 gene of a Japanese patient with AME. PCR amplification and subsequent nucleotide sequencing of the 11βHSD2 gene from the patient and his family members revealed that the patient has a compound heterozygous mutation of this gene. In 1 allele, an undescribed single nucleotide transition in codon 208 in exon 3 resulted in a substitution of arginine to histidine (CGC to CAC: R208H). In the other allele, a deletion of 3 nucleotides in codons 337-338 in exon 5 resulted in a substitution of arginine to histidine and a deletion of tyrosine residue (CGCTAT to CAT: R337H, ΔY338), which has been previously shown to abolish 11βHSD2 enzyme activity. A chloramphenicol acetyltransferase assay-based expression study involving the mineralocorticoid receptor indicated that the novel R208H mutation eliminates the enzymatic activity of 11βHSD2. From the genetic analysis of 50 healthy subjects, the novel R208H mutation was unlikely to be due to polymorphism. Together, these results indicate that this patient is a compound heterozygote for the mutation in the 11βHSD2 gene (R208H and R337H, ΔY338) and that these mutations inactivate the 11βHSD2 function and give rise to clinically manifest AME.