The purpose of this study was to evaluate the recent literature on the genetic characterization of women affected by endometriosis and to evaluate the influence of polymorphisms of the wingless-type mammalian mouse tumour virus integration site family member 4 (WNT4), vezatin (VEZT), and follicle stimulating hormone beta polypeptide (FSHB) genes, already known to be involved in molecular mechanisms associated with the proliferation and development of endometriotic lesions.
Our analysis of the recent literature shows evidence of many genes possibly implicated in different pathogenetic mechanisms of endometriosis (Figure 41).
Figure 41. Pathogenetic targets of the most important genes related to endometriosis.
The wingless-type mammalian mouse tumor virus integration site family member 4 (WNT4) gene is positioned on chromosome 1p36.23-p55 and codifies a protein which is essential in developing the female reproductive system
. It critically regulates the appropriate postnatal uterine maturation, as well as ovarian antra follicle growth
[2]
. The WNT class is an extensive group of secreted glycoproteins, codified through 19 different genes implicated in the WNT signaling pathway
[1]
. WNT-mediated signal transduction pathways address the specific mobilization of groups of genes which are responsible for managing several cellular responses, including cell growth, differentiation, movement, migration, polarity, cell survival and immune response
[1]
. Imperfection in WNT4 activity play role in the development of three important organs deriving from the primordial urogenital ridge- the kidneys, adrenal glands and gonads
[1]
. This may demonstrate the significant position of WNT4 at an early embryological stage of development. The loss of WNT4 in knockout mice determines the total absence of the Mullerian duct and its derivates
[3]
. Apart from being crucial for epithelial-stromal cell communication in the endometrium, WNT signalling is likely important for endometrial maturation an differentiation and embryonic implantation
[7]
. An association between endometriosis and markers located in or near WNT4 has been highlighted in a number of extensive studies on gene mapping
. The expression of WNT4 has also been detected at the level of the peritoneum, leading to the consideration of a possibile metaplastic hypothesis in promoting the transformation of peritoneal cells into endometriosic cells, through pathways with a role in the development of the female genital tract
[4]
. Pagliardini et al. demonstrated that a single nucleotide polymorphisms (SNP), rs7521902, located 21 kb up/downstream of the WNT4 region, has a susceptibility locus for endometriosis. The functional significance of this SNP in endometriosis remains to be explained
[2]
.
The vezatin (VEZT) gene is located on chromosome 12 locus 12q22; it codifies vexation, a significant element of the cadherin-catenin complex, which plays a crucial role in the formation and sustenance of adherent joints
. According to Kussel-Andermann et al., vezatin was found to be a plasma membrane component with a short extracellular domain, a transmembrane domain and an extended intracellular domain. Its intracellular domain connects to myosin VIIA as part of the adherent junctional complex in epithelial cells
[11]
. Furthermore, several studies on co-immunoprecipitation showed that the system between vezatin and myosin VIIA is able to interact with the system between E-cadherin and catenina, although the specificity of this interaction remains to be determined
. Also, VEZT is fundamental for implantation; embryos from mice with silenced VEZT cannot develop after the blastocyst stage, because of loss of adhesion between cells
[14]
. It has been highlighted that VEZT protein is extensively expressed in human endometrium and myometrium. The mRNA expression of adherents junction members is also enhanced in the secretory phase with respect to the proliferative phase. This indicates the progesterone could be responsible for activating cell-to-cell adhesion
[10]
. The VEZT promote does not contain a reaction point for the progesterone receptor (PR), but it contains a nuclear factor kappa B (NF-kB) binding site. As a pro-inflammatory transcription factor, NF-kB is involved in the pathogenesis of endometriosis, showing cycle control in the endometrium and reciprocal management with PR
[15]
. Considering the studied physiological roles of VEZT, its potential for a functional role in endometriosis is a likely option, since VEZT has been demonstrated to be upregulated in ectopic endometrium with respect to eutopic endometrium in patients suffering from endometriosis
.
The follicle-stimulating hormone beta polypeptide (FSHB) gene, positioned on chromosome 11 locus 11p14.1, codifies subunit b of the hormone-specific-follicle-stimulating hormone (FSH) with a crucial role in the growth of ovarian follicles and production of estrogens
. Recently, some evidence for an association between endometriosis and SNPs of FSHB was reported in independent targets from the UK Biobank, firmly supporting this result
[18]
. FSH and luteinizing hormone (LH) are related gonodotropin hormones sharing the same alpha subunit. A connection between these SNPs on chromosome 11 with concentrations of both hormones indicates a common mechanism of regulation, with both being key elements in managing follicle development in the ovary, influencing estradiol release during the proliferative phase of the cycle and contributing to a role for estradiol in endometriosis risk
[17]
. Data from the ENCODE project show that the SNP rs11031006 modifies the sequence of 11 protein-binding motifs, including that of estrogen receptor alfa, with a possibile effect on hormonal feedback inhibition. Recently, allele G of this SNP has been proven to be significantly associated with higher levels of serum FSH
[19]
.