A NEW COMPOUND HETEROZYGOUS MUTATION IN THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2 GENE IN A CASE OF APPARENT MINERALOCORTICOID EXCESS

Apparent mineralocorticoid excess (AME) characterized by early-onset h ypertension and hypokalemia is due to congenital deficiency of 11 beta -hydroxysteroid dehydrogenase (11 beta HSD). Two isoforms of human 11 beta HSD are known, and the type 2 isoform (11 beta HSD2) has been rec ently shown to be responsible for AME. In this study we have analyzed the 11 beta HSD2 gene of a Japanese patient with AME. PCR amplificatio n and subsequent nucleotide sequencing of the 11 beta HSD2 gene from t he patient and his family members revealed that the patient has a comp ound heterozygous mutation of this gene. In 1 allele, an undescribed s ingle nucleotide transition in codon 208 in exon 3 resulted in a subst itution of arginine to histidine (CGC to CAC: R208H). In the other all ele, 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, Delta Y338), which has been previously shown to abolish 11 beta RSD2 enzyme activity. A chloramphenicol acety ltransferase assay-based expression study involving the mineralocortic oid receptor indicated that the novel R208H mutation eliminates the en zymatic activity of 11 beta HSD2. From the genetic analysis of 50 heal thy subjects, the novel R208H mutation was unlikely to be due to polym orphism. Together, these results indicate that this patient is a compo und heterozygote for the mutation in the 11 beta HSD2 gene (R208H and R337H, Delta Y338) and that these mutations inactivate the 11 beta HSD 2 function and give rise to clinically manifest AME.