Saudi Team Identifies Aberrant Genes Involved in Surplus X Chromosome Syndromes

Researchers in Saudi Arabia have used stem cell analysis to improve understanding of the causes behind surplus X chromosomes, which affects one in every 500 to 1,000 males.

The disease can involve one extra X chromosome (Klinefelter Syndrome) or more than one surplus X chromosomes, referred to as higher grade sex chromosome aneuploidies (HGSs). Symptoms include infertility, enlarged breasts, osteoporosis, diabetes, heart abnormalities, intellectual disability and cancer. Though X inactivation does occur in these syndromes—as it does in normal female —“escape” genes from surplus X chromosome(s) do occur.  

“We generated the largest cohort of induced pluripotent stem cells derived from patient fibroblasts to study the effects of having extra copies of the X chromosome in males,” says King Abdullah University of Science & Technology (KAUST) research scientist Veronica Astro. “We also took advantage of KAUST’s cutting-edge technologies to compare gene expression between these and healthy stem cells to identify the genes that are aberrantly expressed in this genetic condition.”

In a recent issue of Frontiers in Cell and Developmental Biology, the team reports that most escape genes were found in a region of the short arm of the X chromosome called pseudo-autosomal region 1 (PAR1). Eleven genes were linked to progressive severity of symptoms with each extra X chromosome. These genes largely remained active when the researchers programmed the stem cells to develop into pre-liver and pre-pancreas cells. Their activity increased with an increasing number of X chromosomes in the cells.

To further test their stem cells, the researchers also examined differences in gene regulators called transcription factors. They found that a protein called nuclear respiratory factor 1 (NRF1) was overexpressed in the stem cells with extra X chromosomes, with impacts on a gene called zinc finger protein X-linked (ZFX).

“Importantly, we generated the first ever described cellular platform of induced pluripotent stem cells with various degrees of X chromosome aneuploidies that can be exploited to study the consequences of gene overdosage in early embryogenesis,” says bioscientist Antonio Adamo, who led the study.

Further efforts should help reveal the mechanisms behind the characteristics seen in people with Klinefelter syndrome and HGAs. The stem cell platform could also be used to screen drugs for treating these conditions.