Structural analysis of the 11β-hydroxysteroid dehydrogenase type 2 gene in end-stage renal disease.

Mutations in the 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) gene cause a rare form of low-renin hypertension leading to end-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 obtain an estimate its prevalence.

The HSD11B2 gene was analyzed in 587 subjects, including 260 ESRD patients (either dialysis or transplanted) for mutations in the exons 2 through 5 and corresponding intronic regions by polymerase chain reaction (PCR) using appropriate overlapping primers, gel analysis by single strand conformational polymorphism (SSCP), and sequencing of identified migration variants.

The prevalence of single-nucleotide polymorphisms (SNPs) in ESRD patients and controls was 26%. The following genetic variants were found among all subjects investigated: exon 2 T442G (Leu¹⁴⁸/Val, N = 70) and C470A (Thr¹⁵⁶/Thr, N = 67), exon 3 G534A (Glu¹⁷⁸/Glu, N = 69), and exon 5 C1274T (Asp³⁸⁸/Asp, N = 2). Four SNPs were identified in intron 4 only. In the control population, the prevalence of the variants Leu¹⁴⁸ and Thr¹⁵⁶ was 14% each. Glu¹⁷⁸ was 11%, while no variants were found in exon 5. In ESRD patients, the prevalence of the variant Leu¹⁴⁸ was 9%, and Thr¹⁵⁶ was 8%. Glu¹⁷⁸ was 13%, while the Asp³⁸⁸ variant was 0.7%. In patients with a short duration between the time of diagnosis of the renal disease and the onset of ESRD, the prevalence of the Leu¹⁴⁸ and Glu¹⁷⁸ variants was higher than in subjects with slowly progressing renal disease. The 11βHSD2 activity of all of these SNPs is predictably unaltered.

There is a high prevalence of SNPs of the HSD11B2 gene, without causing exonic mutations generating a 11βHSD2 enzyme with altered activity. Based on statistical analyses, the frequency of homozygosity for mutated alleles of the HSD11B2 gene can be derived as <1/250,000 when a Caucasian population is considered.