Researchers have determined how being born with one extra or one less sex chromosome affects genetic expression in various tissues. This provides greater insight into the disease characteristics of Turner syndrome and Klinefelter syndrome.
Males born with an extra X chromosome have Klinefelter syndrome, whereas females born with only one X chromosome have Turner syndrome.
Both syndromes are associated with major life challenges.
Girls and women with Turner syndrome are often short, their ovaries do not function properly and they have impaired spatial awareness, making navigating difficult.
Males with an extra X chromosome and thus Klinefelter syndrome are extra tall. The males may have small testicles, with associated reduced fertility and reduced testosterone production and sex drive. People with Klinefelter syndrome are also often challenged in wanting to make sensible choices.
Now, a new study shows what goes wrong in the genetic expression of several tissues when people are born with one extra or one less X chromosome.
The researchers identified genes that are affected when the number of sex chromosomes does not match.
“Our results indicate why people with one of these syndromes may have fertility problems. Many of the identified genes make sense based on how the syndromes present, but we still lack the smoking gun. With this study, we have found the shadow of the smoking gun,” explains a researcher behind the study, Claus Højbjerg Gravholt, Clinical Professor and Consultant, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital.
The research has been published in Genome Medicine.
Often have other comorbidities
When people have too few or too many sex chromosomes, genetic expression is not balanced, since cells often need to express genes from a very specific number of chromosomes.
If there is one chromosome too many, the genetic expression of some genes becomes too high, and it can become too low if a chromosome is missing.
In a previous study, the researchers showed that having too many or too few sex chromosomes means major changes in both RNA expression and DNA methylation in the blood.
The RNA expression means how genes are expressed as proteins in the cells, and DNA methylation expresses the availability of genes in the genome.
In the new study, the researchers wanted to take the study a step further.
“People with Turner or Klinefelter syndrome have a 4- to 6-fold increased risk of developing type 2 diabetes. Factors relevant to the risk of developing type 2 diabetes can best be identified in muscle and adipose tissue, and we therefore studied DNA methylation and RNA expression in blood, muscle and adipose tissue from people with Turner and Klinefelter syndrome and healthy controls,” says Claus Højbjerg Gravholt.
The researchers determined differences in genetic expression among 36 people with Turner syndrome, 22 people with Klinefelter syndrome, 34 healthy female controls and 16 healthy male controls.
“Observing differences is interesting because we want to understand why people with Turner or Klinefelter syndrome have specific characteristics. Why do they have an increased risk of developing type 2 diabetes? Why are their testes or ovaries not working properly? In this study, we searched for this knowledge in the genes,” explains Claus Højbjerg Gravholt.
Change in genetic expression varies in tissues
The results show that RNA expression is altered in blood, muscle and adipose tissue but that the change is not the same between the three tissues in the two syndromes.
According to Claus Højbjerg Gravholt, this means that learning more about the genetic background for developing Turner or Klinefelter syndrome requires more than studying the genetics in a blood sample and requires studying several tissues to get the full picture.
The results also show that many of the genes located on the X chromosome are downregulated among people with Turner syndrome but upregulated among people with Klinefelter syndrome.
The researchers identified 14 genes across the tissues that are both upregulated in Klinefelter syndrome and downregulated in Turner syndrome.
“It is perhaps not surprising that genetic expression is downregulated if you have one less X chromosome and upregulated if you have one extra X chromosome. But no one demonstrated this before us. In addition, we can see which genes are especially affected, and this provides insight into the disease mechanisms,” says Claus Højbjerg Gravholt.
Some genes have a role in both syndromes
The genes identified include the KDM6A gene, which is involved in methylating the DNA and is therefore an obvious culprit in the differences in the DNA methylation patterns among people with either syndrome.
KDM6A is also involved in developing gametes, and this may explain the reduced fertility among people with the two syndromes.
The researchers also identified changes in the expression of the XIST gene in the two syndromes. XIST plays a crucial role in inactivating one sex chromosome. XIST is therefore also upregulated in Klinefelter syndrome and downregulated in Turner syndrome. The TSIX gene plays the opposite role, and the researchers found that it was also oppositely regulated up or down.
A third gene identified is the SLC16A2 gene, which is also affected by the presence of one extra or one less sex chromosome. SLC16A2 plays a crucial role in developing the nervous system.
A well-known fact is that people with either Turner or Klinefelter syndrome have problems with neurocognitive functioning, so it makes sense that the dysregulation of SLC16A2 affects the development of these special characteristics.
“Many of the genes make good sense, but we still need to establish the direct link between having one extra sex chromosome or one less to changes in genetic expression and then to the specific characteristics of people with the two syndromes. We still cannot prove that part unequivocally,” explains Claus Højbjerg Gravholt.
Research on ovaries and testicles
Claus Højbjerg Gravholt explains that probably many more genes than the 14 are involved in the phenotypic features of the two syndromes, but based on a relatively small number of participants the researchers were only able to find some of the relevant genes.
In future experiments, the researchers therefore hope to identify more genes and also changes in genetic expression in more tissues.
The researchers aim to study cells from the inside of the mouth and bladder and from testes and ovaries.
“The study of testes and ovaries can advance understanding of why people with Klinefelter syndrome and Turner syndrome have such difficulty having children. This may also bring us closer to understanding what is required to make this possible,” concludes Claus Højbjerg Gravholt.