Circular RNA plays a key role in rare chromosome disorders

Breaking new ground 18. okt 2022 3 min Clinical Professor Claus H. Gravholt Written by Kristian Sjøgren

People with the rare chromosome disorders Turner syndrome and Klinefelter syndrome differ in the expression of circular RNA. This is associated with problems throughout the body, affecting the brain, growth, reproduction and other functions. The discovery enables researchers to learn about previously unknown aspects of these rare disorders.

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Very few people are born with too many or too few chromosomes.

Females born with one less X chromosome have Turner syndrome and appear as females. Males born with an extra X chromosome have Klinefelter syndrome (47,XXY) and have male characteristics.

Although it is not beneficial to be born with one extra or one less chromosome, researchers have not thoroughly understood how this affects the body. So far, they have only been able to observe the results.

This is now changing, since researchers have progressed a step further in understanding what happens in the body in Turner syndrome and Klinefelter syndrome.

“Our discovery shows that being born with an extra or one less X chromosome affects an entire regulatory process: some parts of the process are upregulated and others downregulated. This does not change anything for these people today but may in the future, because today we understand better how the body fine-tunes regulation and what happens when this does not work properly,” 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 Frontiers in Genetics.

Differences between Turner syndrome and Klinefelter syndrome

Having too many or too few sex chromosomes results in several more or less clear characteristics.

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 and females 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 when wanting to make sensible choices and can have other neurocognitive deficits.

Claus Højbjerg Gravholt’s research group previously investigated whether too many or too few sex chromosomes can affect the regulation of signalling pathways and proteins body through methylation, in which small methyl groups are added to the DNA and thereby regulate the function of genes.

This research showed that these two syndromes definitely change the regulation of signalling pathways. The researchers continued this line of research in this study.

“We have seen that methylation acts differently in different tissues and would very much like to investigate how this occurs in the ovaries and testicles, but getting people to provide samples we can examine is not straightforward. We therefore chose a different type of study to determine how Klinefelter syndrome and Turner syndrome alter regulation,” says Claus Højbjerg Gravholt.

Studied regulatory RNA

The researchers collected blood samples, muscle biopsies and fat biopsies from people with Klinefelter syndrome and Turner syndrome and from healthy controls.

They examined the samples for differences in circular RNA, a type of single-stranded regulatory RNA that forms a covalently closed continuous loop and is not translated into proteins but instead helps to regulate which messenger RNA (mRNA) is translated into proteins.

Circular RNA was relatively recently discovered, and researchers do not yet know much about its function, only that it probably regulates various functions in the body.

“We thought that since we had previously found that the mRNA expression and methylation differ among people with Turner syndrome and Klinefelter syndrome, then perhaps the entire process that controls regulation in the body may also have been altered,” explains Claus Højbjerg Gravholt.

Circular RNA is out of step

The results show that having too many or too few X chromosomes can affect the entire body’s regulatory process.

The researchers found changes in circular RNA in fat tissue, the muscles and the blood that differ between people with either Klinefelter syndrome or Turner syndrome and people with the normal numbers of chromosomes.

According to Claus Højbjerg Gravholt, this can help to explain why too many or too few X chromosomes can affect the whole body.

“We envision that these changes in circular RNA in muscle cells, fat cells and in the blood are probably also present in brain tissue and other places in the body. The overall change in the regulation of RNA can probably explain why the testicles and ovaries do not work properly and why people with Turner syndrome and Klinefelter syndrome have neurocognitive changes in the brain,” says Claus Højbjerg Gravholt.

Will investigate men’s testicles

The results suggest that the changes in circular RNA especially affect the regulation of microRNA, a type of regulatory RNA that affects whether DNA is translated into proteins.

This link is the next target in the researchers’ work, in which they will investigate specifically how Klinefelter syndrome and Turner syndrome lead to changes in circular RNA and how this further affects microRNA.

The researchers have also collected testicular tissue samples from 13 men with Klinefelter syndrome and will examine them further to confirm that the differences found in fat tissue, blood and muscle are also present there.

“We are focusing on getting down to the molecular level and understanding what exactly is changed in these syndromes. We aim to learn why the brain, testicles and ovaries do not function optimally and what we might be able to do about this. I think that we are making great progress, and in 5 years we will understand much better how these syndromes create problems in the body,” concludes Claus Højbjerg Gravholt.

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