Institute for Stem Cell & Regenerative Medicine

at the University of Washington

2014 Jaconette L. Tietze Young Scientist Research Award

Xinxian Deng, PhD, Acting Instructor, Pathology (Disteche Lab)

Sex-chromosome correction in Klinefelter syndrome induced pluripotent stem cells

Klinefelter syndrome (KS; 47, XXY) is the most common sex chromosome aneuploidy in males affecting about 0.1-0.2% of the male population and the second most common condition caused by the presence of extra chromosomes, only to Down syndrome (trisomy 21). The main phenotypes in some but not all KS individuals are hypogonadism, sterility, some degree of cognitive deficits and delays in motor development. The role of sex-linked genes in KS is not well understood. The extra X chromosome is subject to X inactivation and thus should theoretically not cause any abnormal phenotypes. However, an unexpectedly large number of human X-linked genes (~15%), including genes located within the pseudoautosomal regions (PARs) of the X and Y chromosomes, escape X inactivation. In addition, some escape genes outside the PARs also have Y-linked paralogs. The existence of Y-linked paralogs protects males from abnormal phenotypes found in Turner syndrome associated with a single X chromosome (45, X) and haplo-insufficiency for escape genes. Our hypothesis is that additional copies of genes that escape X inactivation cause abnormal phenotypes in specific tissues such as brain in KS individuals. In this pilot study we plan to establish isogenic XXY, XX and XY iPSCs from KS individuals using a gene-targeting-based chromosome loss method developed by D. Russell (UW Department of Medicine). This approach will allow us to eliminate the noise of genomic variability and to better assess the perturbation of gene expression in XXY individuals, similar to the studies in Down syndrome. Our long-term goal is to identify candidate genes having gene dosage effects in sex chromosome aneuploidy conditions such as KS, which will advance our understanding of their genetic causes and provide potential treatments.