Endocrine Abstracts

Klinefelter syndrome (47,XXY; KS) is a very common chromosomal disorder, affecting 1:500 men and leading to hypergonadotropic hypogonadism as well as an increased incidence of metabolic syndrome. However, our knowledge on the functional role of the supernumerary X chromosome itself and to which extent its origin contributes to the observed pathophysiology is still very limited. Recently we started the EXAKT (Epigenetics, X-Chromosomal features and clinical Applications in Klinefelter syndrome Trial) project which is a Muenster-based prospective study involving Klinefelter patients (n=130), and their parents assessing a wide area of biochemical, physiological and genetic parameters in comparison to age-matched healthy male and female controls (2×n=50).

The aim of the genetic and epigenetic part of the EXAKT project is to obtain information on the paternal or maternal origin and the meiotic disjunction events leading to the presence of a supernumerary X chromosome, the inactivation of the second X-chromosome by the non-coding RNA XIST and the expression of X-linked genes which escape X inactivation.

Determination of the origin of the X chromosome by microsatellite analysis in KS and their parents revealed a nearly equal distribution between the paternal (56%) and maternal (44%) origin of the second X chromosome. Methylation analysis of the XIST promoter displayed a significant higher methylation pattern in KS patients (75%) when compared to women (65%). Moreover analysis of escape genes such as KDM6a in blood RNA samples of KS revealed expression levels comparable to levels detected in women.

The first genetic and epigenetic analyses of KS within the EXAKT project revealed a significantly altered inactivation status and an expression of escapee genes reminiscent of women, indicating a pathophysiological role of the supernumerary X chromosome.

Supported by the IZKF Muenster: CRA03/09.

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.