Klinefelter Syndrome: Scientists Discover Genes behind Surplus X Chromosomes

Consisting of about 20,000 genes, each human cell is an organized industry capable of basic life processes. Information concerning the structure and functions of each human cell is contained within these genes and the genes, in turn, are housed in structures called chromosomes. There are 23 pairs of these chromosomes: Autosomes which control the characters of the organism, except those controlled by the sex chromosomes.

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Klinefelter Syndrome

Klinefelter Syndrome

There is a single pair of sex chromosomes in each cell, XX in females and XY in males. Unlike the gene-poor Y chromosome, the X chromosome contains over 1,000 genes that are essential for proper development and cell viability. Females bear two copies of the X chromosome, resulting in a potentially toxic double dose of X-linked genes. To prevent this toxicity, one of the X chromosomes is inactivated, a phenomenon known as X inactivation.

Some males can also have an extra pair of chromosomes. One in every 500 to 1,000 males is born with one or more extra X chromosomes. For example, males born with Klinefelter syndrome have an extra X chromosome (XXY). Although X-inactivation also occurs in this situation, some X-linked genes in the inactivated chromosome escape inactivation and their activity result in the phenotypical characteristic traits that can be observed in these individuals. These traits include infertility, heart abnormalities, osteoporosis, diabetes, enlarged breasts, intellectual disability, and cancer. Until now scientists have never focused on the culprit genes involved in the characteristic features of individuals with this condition.

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Culprit genes

Research carried out by scientists at KAUST Thuwal, Saudi Arabia has been able to trace the location of the culprit genes which escaped X-inactivation. Using stem cells, reprogrammed from people with this condition, their research showed that most escape genes were found in a region of the short arm of the X chromosome called pseudo-autosomal region 1 (PAR1). Out of the 16 genes discovered in this region, 11 genes were found to remain active when the researchers programmed the stem cells to develop into pre-liver and pre-pancreas cells.

To further test their stem cells, the researchers also examined differences in gene regulators called transcription factors and 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).

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Currently, the team led by bioscientist Antonio Adamo is working on differentiating induced pluripotent stem cells with varying numbers of surplus X chromosomes into disease-relevant cell types—like nerve, heart, pancreas, and sperm cells—to study how extra X chromosomes impact different tissues.

Clinical significance

Understanding the genes involved in the traits observed in syndromes related to surplus X chromosomes will help in the understanding of the mechanism behind the development of the observable traits as well as of drugs against the culprit genes.


The discovery of the specific genes involved in the phenotypical traits observed in conditions involving surplus X chromosomes is a milestone discovery in understanding and treating these conditions. A mystery indeed demystified.

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Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies

X Chromosome Inactivation | Learn Science at Scitable (nature.com)



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