Apparent mineralocorticoid excess-a genetic basis for low renin hypertension.

Apparent mineralocorticoid excess (AME) is a syndrome of juvenile hypertension associated with hyporeninemia, hypoaldosteronemia and hypokalemic alkalosis. AME results from mutations in the HSD11β2 gene encoding 11β-hydroxysteroid dehydrogenase type 2, the enzyme responsible for renal conversion of cortisol to cortisone thereby protecting the mineralocorticoid receptor from cortisol activation. HSD11β2 is a 6-7 kb gene composed of 5 exons which is located on chromosone 16q22. To date, 28 HSD11β2 alleles from 14 kindreds containing 19 patients have been studied. Except for a single patient who was a compound heterozygote for two mutations, all patients were homozygous for one of an additional eight different mutations. Expression studies have been done on 7 of these 10 mutations covering 17 of these 19 patients. Only 2, R208C and R213C, have measurable activity. There is a disparity between the in vitro lack of enzymatic activity and the severity of the disease clinically. For example, 2 sibs with the R208C mutation (13% activity) were severely affected since infancy. Additionally, 2 of the 3 patients with the R337H, Δ338 mutation (0 % activity) are mildly affected not having been treated until 4 to 7 yoa while the 3rd is severely affected having had a stroke at 3 yoa. In 8 of the 13 families with a homozygous mutation, homozygosity is explained by consanguinity (3), endogamy (3) and founder effect (2). In the 5 remaining families, sufficient pedigrees are not available. We studied an Italian child who presented at 10 yrs of age with a history of polyuria, polydipsia and hypertension. Sequence analysis of his HSD11β2 gene revealed two new mutations in exon 4, D244N (GAC to AAC) and L250R (CTC to CGC). This L250R mutation involves the same nucleotide in codon 250 as is involved in the previously reported L250P, L251S mutation (CTC to CCC). The possibility of mutational hot spots within the HSD11β2 gene is suggested by: 1. The involvement of codon 250 in the L250R and L250P, L251S mutations. 2. The involvement of codon 337 in the R337C and the R337H, DY338 mutations. 3. The appearance of the R208C mutation in two tribal families, a Bedouin from Oman and a Native North American from Canada.