Endocrine Abstracts (2012) 29 OC14.5

The muenster EXAKT project: X-inactivation in klinefelter patients

S. Werler1, R. Bongers1, F. Tuettelmann2, M. Zitzmann1, S. Kliesch1 & J. Gromoll1

1Centre of Reproductive Medicine and Andrology, Muenster, Germany; 2Institute of Human Genetics, Muenster, Germany.

Introduction: Klinefelter Syndrome (KS; 47,XXY) is the most common sex chromosome disorder in men, characterized by hypergonadotropic hypogonadism. EXAKT (Epigenetics, X-chromosomal features and clinical Applications in Klinefelter syndrome Trial) is a Muenster-based prospective project involving Klinefelter patients and their parents assessing a wide area of cardiovascular, inflammatory and metabolic factors as well as a broad range of genetic and epigenetic investigations especially regarding X-inactivation that could be disturbed due to the aberrant sex chromosomal constitution. Therefore, we have examined the methylation profile of XIST, which drives X-inactivation, in KS blood samples taking into account the X-chromosomal origin.

Material & methods: Klinefelter blood samples (n=130), male (n=50) and female (n=50) controls; Pyrosequencing; Microsatellite analysis.

Results: X-origin was determined in 80 KS patients: 56% of patients had a paternal origin of the supernumerary X-chromosome, whereas 24% showed a maternal MII origin and 20% MI origin of the extra X. In men, XIST methylation levels reached nearly 100% while in women on average 65% were found, indicating the correct silencing of one of the two X-chromosomes. XIST methylation level in 130 KS patients was 75% on average. The XIST methylation pattern of KS patients with paternal origin of the X-chromosome (74%) resembled that of KS patients with MI origin (73%) and both significantly differed from the methylation pattern of patients with MII X-origin (80%).

Conclusion: In contrast to previous studies, we detected hypermethylation of XIST in KS. The role of the altered XIST methylation pattern remains to be further studied. The higher XIST methylation in KS patients with MII origin points to a disturbed X-inactivation depending on the parental inheritance.

Supported by the IZKF Münster: CRA03/09; and DFG (Grant No. WI2723/4-1).

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.

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