The 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

Autor(es)

Moura-Massari, Vivian Oliveira ^[1] ; Cunha, Flavia Siqueira ^[1] ; Gomes, Larissa Garcia ^[1] ; Diniz Gomes, Diogo Bugano ^[2] ; Miguel Marcondes, Jose Antonio ^[1] ; Madureira, Guiomar ^[1] ; de Mendonca, Berenice Bilharinho ^[1] ; Sartori Sanchez Bachega, Tania A. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Lab Hormonios & Genet Mol LIM 42, Unidade Suprarrenal, Disciplina Endocrinol, Hosp Cl, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Hosp Clin, Dept Clin Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 11, n. 2 FEB 5 2016.
• Citações Web of Science: 2

Resumo

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 5 alpha-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 SRD5A2 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. (AU)

• Processo FAPESP: 05/04726-0 - Caracterização molecular das doenças endócrinas congênitas que afetam o crescimento e o desenvolvimento
• Beneficiário: Ana Claudia Latronico Xavier
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 08/51624-6 - Análise de genes moduladores do fenótipo da forma não clássica da deficiência da 21-hidroxilase
• Beneficiário: Vivian de Oliveira Moura
• Linha de fomento: Bolsas no Brasil - Mestrado
• Processo FAPESP: 14/07878-4 - Avaliação da eficácia dos diferentes testes diagnósticos no programa nacional de triagem neonatal (PNTN) da hiperplasia adrenal congênita por deficiência da 21-hidroxilase (HAC)
• Beneficiário: Tania Aparecida Sartori Sanchez Bachega
• Linha de fomento: Auxílio à Pesquisa - Regular