Estudo dos genes WNT4 E CTNNB1 na síndrome de MAYER-ROKITANSKY-KÜSTER-HAUSER

Abstract

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital malformation of the female genital tract and is the second cause of primary amenorrhea, affecting one in every 5000 female live births. The genetic defect associated with the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome has not been determined. Its elucidation would not only shed light up on the pathogenesis of the MRKH syndrome, but would greatly contribute to the general understanding of the genetic control of human fetal sexual development, specially the female sex, which has always been considered the default pathway. We conducted this study to investigate whether two genes extensively involved with female sexual determination and differentiation - WNT4 and CTNNB1 (-catenin-1, gene) - are affected in patients with Müllerian defects. The gene WNT4 is crucial for maintenance of ovarian structure during fetal life and for Müllerian duct formation. Recently, WNT4 gene mutations were described in patients with Müllerian duct regression and hyperandrogenism. Nevertheless, this finding has not been confirmed in other groups of patients with the MRKH syndrome. -catenin is a key downstream component of both WNTs and AMH (anti-Müllerian hormone) signaling pathways; AMH is directly responsible for Müllerian duct regression in males and leads to -catenin stabilization in periductal mesenchymal cells. -catenin serine/threonine phosphorilation sites are codified by nucleotidic sequences in the exon 3 of the CTNNB1. Mutations affecting this exon protect -catenin protein from degradation, leading to its accumulation in the citoplasm and nucleus, which could ultimately contribute to a putative abnormal regression of the Müllerian ducts. Six female patients with the MRKH syndrome presenting to a Brazilian infertility center were studied. DNA was extracted from peripheral blood and subjected to PCR. After purification of PCR products, direct DNA automated sequencing to screen for nucleotide variation of the five coding exons of the WNT4 and the exon 3 of the CTNNB1 gene was performed. No significant nucleotidic variations on the WNT4 gene or on the exon 3 of CTNNB1 were found in this group of MRKH patients. In our study we concluded that WNT4 gene mutations are not associated with the MRKH syndrome. Screening for WNT4 mutations should be reserved for patients presenting with Müllerian defects and associated hyperandrogenism. Mutations on the exon 3 of CTNNB1 gene are an unlikely cause of the MRKH syndrome. Other dowstream effector molecules of the WNTs and AMH signaling pathways should be investigated in attempt to elucidate the genetic defect associated with the MRKH syndrome.