Klinelter syndrome (KS) is caused by supernumery X chromosomes in the male. It is the most common chromosomal aberration in men. The additional X chromosome(s) are thought to be acquired through defective meiotic segregation, studies of which form the basis of research in the Cohen and Schimenti labs. Drs. Paduch and Schlegel are experts in the treatment of infertility in KS patients and in the understanding of the hormonal and cellular basis for different aspects of the disease.
For further information on KS and treatment of infertility see: Reproduction in men with Klinefelter Syndrome: the past, the present and the future. By Darius Paduch, Alexander Bolyakov, Alex Travis, and Paula Cohen. Seminars in Reproductive Medicine (2009) 27: 137-148 DOWLOAD
Figure 1. Human testis section stained for Sertoli Cells (FITC– green) and Ledig cells (texas red – CYP19). Klinefelter syndrome patients show elevated Cyp19 aromatase protein localization. Data courtesy of Dr. Darius Paduch.
Copyright Darius Paduch, 2012
A new study from Andrew Grimson's lab, in collaboration with Paula Cohen's lab, has identified a key pathway required for maintenance of sex chromosome telomere integrity. Using conditional knockout mice for Dicer and Dgcr8, two key enzymes required for small RNA processing, Modzelewski et al (2015) show that loss of small RNAs during prophase I leads to telomere fusion events specifically involving the X and Y chromosomes. For further information, see the May edition of Journal of Cell Science
A recent publication by Dabaja et al (2015) has identified key cell:cell interactions that are necessary to establish normal profiles of one key microRNA, miR202-5p, in Sertoli cells. This is the first example of a germ cell regulatory interaction that is necessary for miR expression in neighboring somatic cells of the testis
The lab of Center member John Schimenti recently identified the DNA damage checkpoint pathway responsible for culling oocytes that fail to repair double stranded breaks (DSBs) that occur during meiosis or which arise in a female's oocyte pool (Bolcun-Filas et al, Science 343:533-536, 2014). Using combinations of mutants involved in recombination and DNA damage responses, they found that this pathway involves signaling of checkpoint kinase 2 (CHK2) to both p53 and p63. Disruption of this checkpoint pathway restored fertility to females that normally would be deficient of all oocytes due to defects in meiotic recombination or exposure to radiation. This discovery opens the way to using available CHK2 inhibitors to protect the oocytes of women undergoing cancer therapy that would normally cause infertility.