Researchers discover genes involved in increased risk of egg aneuploidy

Researchers, in a 2024 study, have discovered that mutations in genes that code for specialized proteins called kinesins could lead to increased risk of aneuploidy and accelerate the aging process.

Aneuploid embryos, which have an abnormal number of chromosomes, are a major cause of miscarriages and implantation failures.

Aneuploidy occurs when chromosomes separate incorrectly during meiosis, the process that reduces chromosome numbers from 46 to 23 in egg and sperm cells. This separation is controlled by the spindle apparatus, a cellular structure that anchors to chromosomes and pulls them apart.

Aneuploidy is closely linked to female age, but in some women there are specific genetic mutations that can compromise key structures that are needed for meiosis.

A new study by Biswas et al. (2024) identified that mutations in genes that code for a group of proteins known as kinesins are associated with an increased risk of egg aneuploidy.

For more background on egg aneuploidy, check out my post Chromosomal errors in IVF: What is aneuploidy and what causes it?

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In this study, the researchers identified 178 patients that had a high or low risk of aneuploidy for their age.

The researchers sequenced the DNA of the patients to find genes that were different (variants) that could explain the high or low rates of aneuploidy. From this, they identified variants in the KIF20A and KIF18A genes.

The genes KIF20A and KIF18A encode proteins known as kinesins, which have important motor functions within cells. Essentially, these proteins act like little engines that help move various components inside the cell, especially during cell division. During the process of meiosis, these kinesins are responsible for helping to move factors needed for chromosome separation. If the kinesins don’t work correctly because of mutations then this movement can go wrong, leading to an incorrect number of chromosomes in the egg.

You can see kinesins in action during chromosome separation below, around the 1:30 mark (courtesy of WEHImovies on Youtube). They “walk” along tubes called microtubules that anchor onto chromosomes and separate them, carrying special factors needed for this separation. For more info on this process, check my post on the causes of aneuploidy.

To test that the genes for these kinesins were involved in aneuploidy, the researchers performed experiments in mice. They found that both inhibiting the normal function of KIF18A and KIF20A proteins in mouse eggs and inserting extra copies of their mutant genes increased the rates of aneuploidy.

This showed that KIF18A and KIF20A variants were indeed involved in aneuploidy! So mutations in these kinesins leads to aneuploidy.

So how common are these mutations anyway? The KIF20A gene variant was extremely rare and found in only one out of 178 patients, while the KIF18A variant was more common, appearing in 17 out of 178 patients.

Because of how common the KIF18A variant was, the researchers developed a mouse model using CRISPR technology to mimic this human genetic variant. In this model, they found that the KIF18A variant led to increased aneuploidy in mouse eggs, but only in moderately older mice, suggesting that this variant may accelerate the aging process in egg cells.

This shows that the KIF18A variant could cause higher levels of aneuploidy with age, so the maximum effect of this mutation might only be seen when combined with other aging processes in the egg, like the loss of the cohesin protein that helps keep chromosomes together.

The researchers note that mice with two copies of the variant (homozygous) didn’t start to show problems until they reached 20 weeks of age, which is equivalent to a woman in her early 30s. This suggests that these variants might only cause increased aneuploidy in women starting in their early 30s.

Reference

Biswas L, Tyc KM, Aboelenain M, Sun S, Dundović I, Vukušić K, Liu J, Guo V, Xu M, Scott RT Jr, Tao X, Tolić IM, Xing J, Schindler K. Maternal genetic variants in kinesin motor domains prematurely increase egg aneuploidy. Proc Natl Acad Sci U S A. 2024 Nov 5;121(45):e2414963121. doi: 10.1073/pnas.2414963121. Epub 2024 Oct 30. PMID: 39475646; PMCID: PMC11551467.

 

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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