CeRA wins once again DGA research award

German society for Andrology (DGA) yearly awards a research grant annotated with 10000 Euro supporting young researchers. Title of the 2016 announcement was “Andrologie - ein multidisziplinäres Forschungsfeld: Vom Knaben bis zum Greis, von der Stammzelle bis zum Spermium”. After CeRA winning the award in 2009 (Frank Tüttelmann) and in 2011 (Jonas Maliske) once again the prize goes to Münster. This time the clinician Jann F. Cremers wins the award for the research project “Fertility in the ageing male (FAME)”.

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"RHOX transcription factor genes are mutated in infertile men"

Infertility affects 10-15% of couples with the wish for parenthood, and nearly half of these cases can be attributed to a male factor. That means around 7 percent of all males of reproductive age have fertility problems. In a collaborative study, recently published by Human Molecular Genetics, the researchers provide evidence that mutations in the reproductive homeobox (RHOX) family of transcription factors are linked to infertile men with severely low sperm count.

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"Successful identification of an X-linked gene causing meiotic arrest and azoospermia"

In this collaborative study recently published in the New England Journal of Medicine and led by Frank Tüttelmann (Institute of Human Genetics and Centre of Reproductive Medicine and Andrology, Münster, Germany) and Alexander Yatsenko (Magee-Womens Research Institute, Pittsburgh, USA), mutations in the X-linked testis-expressed gene 11 (TEX11) were identified as cause for meiotic arrest and azoospermia.

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"Epigenetics and male fertility – not all sperm are created equal"

What is epigenetics and why is it important for reproduction?

Epigenetics relates to changes in gene expression which are not caused by changes in gene sequence. Epigenetic regulation can involve several mechanisms, the most studied being modification of histone residues and methylation of cytosine nucleotides. DNA methylation is extremely important for a process called genetic imprinting which takes place in placental mammals. Imprinted genes are biallelic genes which, due to the epigenetic inactivation of one of the copies either in the sperm or the oocytes, are expressed only through the maternal or the paternal allele. After fertilization, the embryo undergoes a genome wide wave of demethylation which erases most of the epigenetic marks inherited from the gametes, but does not affect imprinted genes. These marks are usually maintained in the somatic lineages of the offspring. In the germline, however, these imprints must be reprogrammed, therefore primordial germ cells undergo a second genome wide wave of demethylation (now including imprinted genes), followed by de novo methylation.   
In recent years, several studies have indicated a possible link between epigenetic factors in sperm and male infertility. Some studies have suggested a higher prevalence of imprinting disorders in children born after assisted reproductive techniques (ART). Aberrant imprinting in sperm DNA has been associated with abnormal sperm parameters (including reduced sperm count and morphological abnormalities), increased rates of stillbirths and spontaneous abortions, and the levels of DNA methylation in sperm have been suggested to predict ART outcome.

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"What do Klinefelter patients tell us about FSH regulation in men?"

  • Regulation of FSH production at the transcriptional level – and its alteration
    The pituitary follicle-stimulating hormone (FSH) plays a key role in human reproduction. It promotes follicular maturation and estrogen production in females, whereas in males, it promotes proliferation of Sertoli cells in immature testes and maintains normal spermatogenesis in adults. FSH consists of two subunits. Encoded by the FSHB gene, the transcription of its β-subunit, represents the rate-limiting step in FSH production. Despite previous efforts to study the determinants of FSHB promoter activation, the knowledge about factors driving the gene’s transcription is very limited.
  • Klinefelter’s syndrome
    Klinefelter’s syndrome (KS) is the most frequent genetic cause of male infertility. The syndrome is caused by a numerical sex chromosomal aberration (47, XXY or higher-grade aneuploidies and mosaicisms). Patients typically display small firm testes and azoospermia, while other symptoms including eunuchoid tall stature, gynaecomastia, display a broad interindividual phenotypic variability. Due to deficient testicular function and hence the absence of negative feedback regulation along the hypothalamus-pituitary-gonadal axis by the gonadal steroids and Inhibin B, adult Klinefelter individuals share the endocrine hallmark of hypergonadotropic FSH levels. This leads to the question: In what manner does the genetic variant impact FSH levels in Klinefelter patients?

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