Variations in the 3'UTR of the CYP21A2 Gene in Heterozygous Females with Hyperandrogenaemia

Abstract

Heterozygosity for CYP21A2 mutations in females is possibly related to increased risk of developing clinical hyperandrogenism. The present study was designed to seek evidence on the phenotype-genotype correlation in female children, adolescents, and women with CYP21A2 mutations and variants in the 3'UTR region of the gene. Sixty-six patients out of the 169 were identified as carriers of CYP21A2 mutations. Higher values of stimulated 17 hydroxyprogesterone (17-OHP) levels were found in the carriers of the p.Val281Leu mutation compared to the carriers of other mutations (mean: 24.7 nmol/l versus 15.6 nmol/l). The haplotype of the ^∗52C>T, ^∗440C>T, and ^∗443T>C in the 3'UTR was identical in all heterozygous patients with p.Val281Leu and the haplotype of the ^∗12C>T and ^∗52C>T was identical in all heterozygous patients with the p.Gln318^∗. In conclusion, hyperandrogenaemic females are likely to bear heterozygous CYP21A2 mutations. Carriers of the mild p.Val281Leu mutation are at higher risk of developing hyperandrogenism than the carriers of more severe mutations. The identification of variants in the 3'UTR of CYP21A2 in combination with the heterozygous mutation may be associated with the mild form of nonclassic congenital adrenal hyperplasia and reveal the importance of analyzing the CYP21A2 untranslated regions for the appropriate management of this category of patients.

Figure 1

CYP21A2 mRNA secondary structure prediction. (a) and (b) predicted CYP21A2 mRNA secondary structures showing the MFE positional and centroid positional entropy, respectively, for the wild type, 281L/^∗52/^∗440/^∗443 mutant, and 318Ter/^∗12/^∗52 mutant. (c) Minimum free energy (MFE) and centroid secondary structure MFE values. mRNA secondary structures values with 1 kcal/mol above the minimum MFE observed in wild type are considered responsible for the destabilisation of the structure [48]. (d) Positional entropies for the wild type, 281L/^∗52/^∗440/^∗443 mutant, and 318Ter/^∗12/^∗52 mutant. Locations of the variations are indicated. 281L/^∗52/^∗440/^∗443 mutant variations are indicated with red colour. 318Ter/^∗12/^∗52 mutant variations are indicated with green colour. ^∗52 variation which is common in the two mutants is indicated with black colour.