Abstract
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a rare disease characterized by congenital aplasia of uterus and vagina. Although many studies have investigated several candidate genes, up to now none of them seem to be responsible for the aetiology of the syndrome. In our study, we identified differences in gene expression profile of in vitro cultured vaginal tissue of MRHKS patients using whole-genome microarray analysis. A group of eight out of sixteen MRKHS patients that underwent reconstruction of neovagina with an autologous in vitro cultured vaginal tissue were subjected to microarray analysis and compared with five healthy controls. Results obtained by array were confirmed by qRT-PCR and further extended to other eight MRKHS patients. Gene profiling of MRKHS patients delineated 275 differentially expressed genes, of which 133 downregulated and 142 upregulated. We selected six deregulated genes (MUC1, HOXC8, HOXB2, HOXB5, JAG1 and DLL1) on the basis of their fold change, their differential expression in most patients and their relevant role in embryological development. All patients showed upregulation of MUC1, while HOXB2 and HOXB5 were downregulated, as well as Notch ligands JAG1 and DLL1 in the majority of them. Interestingly, HOXC8 was significantly upregulated in 47% of patients, with a differential expression only in MRKHS type I patients. Taken together, our results highlighted the dysregulation of developmental genes, thus suggesting a potential alteration of networks involved in the formation of the female reproductive tract and providing a useful clue for understanding the pathophysiology of MRKHS.
Highlights
Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) is a rare disease characterized by congenital aplasia of the uterus and the upper two-thirds of the vagina, occurring in 1 out of 4500 female births
It has been proposed that inappropriate production of Anti-Mullerian Hormone (AMH) in female embryos might induce a partial regression of the Mullerian duct, causing vaginal agenesis [4]
Total RNA obtained by cell cultures derived from vaginal mucosa of eight MRKHS patients, five with type I MRKHS and three with type II MRKHS (Table 1, patients numbered from 1 to 8), and from vaginal mucosa of five healthy controls were analysed by microarray
Summary
Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) is a rare disease characterized by congenital aplasia of the uterus and the upper two-thirds of the vagina, occurring in 1 out of 4500 female births. Normal secondary sexual characteristics and karyotype (46, XX) have been shown in MRKHS women. This syndrome may occur as isolated (type I), or associated with other malformations, mainly renal, skeletal and hearing defects, and, to a lesser extent, cardiac or digital defects (type II), indicated as MURCS association (Mullerian duct aplasia, Renal dysplasia and Cervical Somite anomalies) [1,2]. It has been proposed that inappropriate production of AMH in female embryos might induce a partial regression of the Mullerian duct, causing vaginal agenesis [4]. Rall et al [6] hypothesized that an embryonic exposure to AMH signalling, caused by high levels of oestrogens or by deregulated expression of related genes, might occur in these patients
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