A combination of transcriptome and methylation analyses reveals embryologically-relevant candidate genes in MRKH patients

Abstract

BackgroundThe Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is present in at least 1 out of 4,500 female live births and is the second most common cause for primary amenorrhea. It is characterized by vaginal and uterine aplasia in an XX individual with normal secondary characteristics. It has long been considered a sporadic anomaly, but familial clustering occurs. Several candidate genes have been studied although no single factor has yet been identified. Cases of discordant monozygotic twins suggest that the involvement of epigenetic factors is more likely.MethodsDifferences in gene expression and methylation patterns of uterine tissue between eight MRKH patients and eight controls were identified using whole-genome microarray analyses. Results obtained by expression and methylation arrays were confirmed by qRT-PCR and pyrosequencing.ResultsWe delineated 293 differentially expressed and 194 differentially methylated genes of which nine overlap in both groups. These nine genes are mainly embryologically relevant for the development of the female genital tract.ConclusionOur study used, for the first time, a combined whole-genome expression and methylation approach to reveal the etiology of the MRKH syndrome. The findings suggest that either deficient estrogen receptors or the ectopic expression of certain HOXA genes might lead to abnormal development of the female reproductive tract. In utero exposure to endocrine disruptors or abnormally high maternal hormone levels might cause ectopic expression or anterior transformation of HOXA genes. It is, however, also possible that different factors influence the anti-Mullerian hormone promoter activity during embryological development causing regression of the Müllerian ducts. Thus, our data stimulate new research directions to decipher the pathogenic basis of MRKH syndrome.

Decidualization is Impaired in Endometrial Stromal Cells from Uterine Rudiments in Mayer-Rokitansky-Küster-Hauser Syndrome

“…Earlier studies have indicated that, potentially, hormone receptors may be dysfunctional in patients with the syndrome [2, 13]. A recent whole-genome analysis of our MRKHS patient population revealed overexpression of ESR1 and PGR in tissue from uterine rudiments [13]. A subsequent histological and immunohistochemical study revealed that the proliferative capacity of endometrium from MRKHS patients was significantly reduced [2].…”

“…Earlier studies have indicated that, potentially, hormone receptors may be dysfunctional in patients with the syndrome [2, 13]. A recent whole-genome analysis of our MRKHS patient population revealed overexpression of ESR1 and PGR in tissue from uterine rudiments [13].…”

“…We therefore studied the rudimentary organ itself and demonstrated in earlier histological and immunohistochemical work that the proliferative capacity of endometrium was significantly reduced in uterine rudiments from MRKHS patients [2]. In a first-ever study using combined whole-genome expression and methylation to investigate the potential role of epigenetic factors, we found, inter alia , that hormone receptors were overexpressed in uterine rudiments from MRKHS patients [13]. The observed local overexpression of estrogen receptor 1 (ESR1) and progesterone receptor (PGR) may have resulted from a positive feedback loop to compensate for functional restrictions, as proliferation capacity is significantly reduced.…”

“…Moreover, increased ESR1 expression may have resulted in aberrant activation of the anti-Müllerian hormone (AMH) promoter during embryonic development of the female reproductive tract and, ultimately, regression of the Müllerian ducts [13], thus constituting a functional, local cause for the observed absence of the uterine organ. This hypothesis is supported by our histological and immunohistochemical analyses of the structure of uterine rudiments from MRKHS patients [2].…”

The rectovaginal septum: visible on magnetic resonance images of women with Mayer-Rokitansky-Küster-Hauser syndrome (Müllerian agenesis)

“…One in 4,500 women in the USA suffers from Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, which is defined by aplasia of the Müllerian-derived portion of the vagina and of the uterus [15]. Magnetic resonance imaging (MRI) is often used to help identifying secondary anomalies related to MRKH syndrome and has become a useful tool in its preoperative diagnostics.…”