T. Zaehner et al., Structural analysis of the 11 beta-hydroxysteroid dehydrogenase type 2 gene in end-stage renal disease, KIDNEY INT, 58(4), 2000, pp. 1413-1419
Background. Mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 (1
1 beta HSD2) gene cause a rare form of low-renin hypertension leading to en
d-stage renal disease (ESRD) in some affected subjects. To date, no search
for mutations in the HSD11B2 gene was performed in a large population to ob
tain an estimate its prevalence.
Methods. The HSD11B2 gene was analyzed in 587 subjects, including 260 ESRD
patients (either dialysis or transplanted) for mutations in the exons 2 thr
ough 5 and corresponding intronic regions by polymerase chain reaction (PCR
) using appropriate overlapping primers, gel analysis by single strand conf
ormational polymorphism (SSCP), and sequencing of identified migration vari
ants.
Results. The prevalence of single-nucleotide polymorphisms (SNPs) in ESRD p
atients and controls was 26%. The following genetic variants were found amo
ng all subjects investigated: exon 2 T442G (Leu(148)/Val, N = 70) and C470A
(Thr(156)/Thr, N = 67), exon 3 G534A (Glu(178)/Glu, N = 69), and exon 5 C1
274T (Asp(388)/Asp, N = 2). Four SNPs were identified in intron 4 only. In
the control population, the prevalence of the variants Leu(148) and Thr(156
) was 14% each. Glu(178) was 11%, while no variants were found in exon 5. I
n ESRD patients, the prevalence of the variant Leu(148) was 9%, and Thr(156
) was 8%. Glu(178) was 13%, while the Asp(388) variant was 0.7%. In patient
s with a short duration between the time of diagnosis of the renal disease
and the onset of ESRD, the prevalence of the Leu(148) and Glu(178) variants
was higher than in subjects with slowly progressing renal disease. The 11
beta HSD2 activity of all of these SNPs is predictably unaltered.
Conclusions. There is a high prevalence of SNPs of the HSD11B2 gene, withou
t causing exonic mutations generating a 11 beta HSD2 enzyme with altered ac
tivity. Based on statistical analyses, the frequency of homozygosity for mu
tated alleles of the HSD11B2 gene can be derived as <1/250,000 when a Cauca
sian population is considered.