Mechanisms of disorders of germ cell development in testicular dysgenesis syndrome - EDMaRC

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Mechanisms of disorders of germ cell development in testicular dysgenesis syndrome

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Main Researcher: Ewa Rajpert-De Meyts
MSc, PhD, Senior Scientist, Research group leader

Other Researchers:  Sofia B. Winge, Marlene D. Dalgaard, Anne Jørgensen, Niels Erik Skakkebæk, Kristian Almstrup and Anders Juul.  
Objective: To better understand the interplay between genes and environment during normal fetal development and identify the target genes.

Description: Denmark is among the countries with the highest incidence of testicular germ cell cancer and other disorders within the testicular dysgenesis syndrome (TDS). The epidemiological trends indicate that human male germ cells are vulnerable to environmental factors during fetal life, but genetic predisposition also plays an important role. The mechanisms remain poorly understood, primarily, because it is difficult to study prenatal events and there are no suitable animal models.
To identify genetic targets, we are going to use, as a model, severe types of TDS, known as disorders of sex differentiation (DSD), which are genetically determined. Some of these disorders (e.g. mixed gonadal dysgenesis and partial androgen insensitivity syndrome) have a very high risk of germ cell malignancy, while other disorders (e.g. Klinefelter syndrome) are characterized by progressive germ cell demise resulting in infertility.
We have collected DNA and tissue samples from subjects with these disorders at various stages of development, including a series of fetal tissue samples.
We shall perform comparative studies of gene expression in these tissues and in normal age-matched controls. The studies are focusing on the somatic niche, composed of Sertoli-, Leydig- and peritubular cells, which is crucial for the proper development of germ cells. We have also constructed a panel of genes involved in sex differentiation; including variants identified in our previous genome-wide study of TDS. We will investigate these genes in DSD subjects for possible mutations. Candidate genes will be subsequently validated in larger patient cohorts, with cancer or with infertility caused by lack of germ cells. Selected pathways will be mechanistically explored in experimental studies to investigate their possible direct involvement in cell proliferation, differentiation and malignant transformation.

Outcome: The sequencing of the candidate genes in DSD patients and transcriptome of cell populations in Klinefelter syndrome were performed in 2015. The analysis of data is in progress, with the results expected at the end of 2016. Further mechanistic studies of selected pathways will be continued in 2017.

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