Etiology and pathogenesis of the MRKH syndrome, a female genital malformation

• Applicants: Professorin Dr. Sara Brucker; Professor Dr. Oliver Kohlbacher; Professor Dr. Olaf Riess
• Subject Area: Gynaecology and Obstetrics
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 351381475

The pathogenesis of the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a rare malformation of the female genitalia, is widely unknown. Because of yet unresolved reasons the development of the female reproductive tract out of the Muellerian ducts stops during the early embryonal phase. This inhibition malformation leads to the absence of the uterus as well as the upper two thirds of the vagina in otherwise phenotypically normal females , as ovaries develop normal with regular hormone production (type I). Associated malformations additional to the utero-vaginal malformations, such as malformations of the urological and/or skeletal system, can occur (type II).Previous studies could find some genetic variants, but the molecular pathogenesis of the MRKH syndrome remains unclear. Up to now, research concentrated only on the analyses of patient´s blood samples and hypothesis driven single-gene analyses. Here we will take advantage of our worldwide unique collection of biomaterial of trios (sporadic patients and their parents), monocygotic twins and familial cases, which is available at the Department of Women´s Health Tuebingen. We will apply multilevel omics analyses, advanced bioinformatics data mining and functional analyses in innovative shRNA transgenic mouse models to i) identify, ii) validate and iii) characterize new genes involved in MRKH pathogenesis. Besides blood, we will investigate the affected organ itself for genetic alterations, concentrating not only on one causative variant, but considering a polygenic cause in which not always one but often multiple different genes within the same pathway are affected. With exome-wide genetic screening of the trios we will find de novo germline mutations; by exome sequencing of blood and uterine rudiment tissue of monozygotic twins and sporadic cases we will detect somatic mutations in the altered tissue. To assess whether these variants have an impact on the regulatory level, we will perform transcriptome sequencing. Constantly comprehensive integrative bioinformatics analyses will be conducted to pinpoint and prioritize candidate genes, which will be functionally tested in shRNA transgenic mice, which can be rapidly generated within 4-5 month after identification of a candidate gene. In the long term, these findings might even lead to preventive approaches for the vulnerable phase in early pregnancy, allowing the development of a normal uterus and so the possibility of own child-bearing and preventing e.g. kidney malformations thereby maximizing quality of life.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Lars Zender