Open AccessThe Presence of Clitoromegaly in the Nonclassical Form of 21-Hydroxylase Deficiency Could Be Partially Modulated by the CAG Polymorphic Tract of the Androgen Receptor Gene
Author(s) -
Vivian Oliveira Moura-Massari,
Flávia Siqueira Cunha,
Larissa Gomes,
Diogo Bugano Diniz Gomes,
José Antônio Miguel Marcondes,
Guiomar Madureira,
Berenice B. Mendonca,
Tânia A. S. S. Bachega
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0148548
Subject(s) - genotype , androgen receptor , allele , medicine , 21 hydroxylase , hpaii , endocrinology , androgen , nefazodone , allele frequency , multiplex ligation dependent probe amplification , biology , genetics , congenital adrenal hyperplasia , gene , receptor , exon , dna methylation , gene expression , prostate cancer , cancer , hormone , serotonin , fluoxetine
Background In the nonclassical form (NC), good correlation has been observed between genotypes and 17OH-progesterone (17-OHP) levels. However, this correlation was not identified with regard to the severity of hyperandrogenic manifestations, which could depend on interindividual variability in peripheral androgen sensitivity. Androgen action is modulated by the polymorphic CAG tract (nCAG) of the androgen receptor (AR) gene and by polymorphisms in 5α-reductase type 2 ( SRD5A2 ) enzyme, both of which are involved in the severity of hyperandrogenic disorders. Objectives To analyze whether nCAG-AR and SRD5A2 polymorphisms influence the severity of the nonclassical phenotype. Patients NC patients (n = 114) diagnosed by stimulated-17OHP ≥10 ng/mL were divided into groups according to the beginning of hyperandrogenic manifestations (pediatric and adolescent/adult) and CYP21A2 genotypes (C/C: homozygosis for mild mutations; A/C: compound heterozygosis for severe/mild mutations). Methods CYP21A2 mutations were screened by allelic-specific PCR, MLPA and/or sequencing. HpaII -digested and HpaII -undigested DNA samples underwent GeneScan analysis to study nCAG, and the S RD5A2 polymorphisms were screened by RLFP. Results Mean nCAG did not differ among pediatric, adolescent/adult and asymptomatic subjects. In the C/C genotype, we observed a significantly lower frequency of longer CAG alleles in pediatric patients than in adolescent/adults (p = 0.01). In patients carrying the A/C genotype, the frequencies of shorter and longer CAG alleles did not differ between pediatric patients and adolescent/adults (p>0.05). Patients with clitoromegaly had significantly lower weighted CAG biallelic mean than those without it: 19.1±2.7 and 21.6±2.5, respectively (p = 0.007), independent of the CYP21A2 genotype's severity. The SRD5A2 polymorphisms were not associated with the variability of hyperandrogenic NC phenotypes. Conclusions In this series, we observed a modulatory effect of the CAG-AR tract on clinical manifestations of the NC form. Although the NC form is a monogenic disorder, our preliminary data suggested that the interindividual variability of the hyperandrogenic phenotype could arise from polygenic interactions.