Gene CENATAC responsible for aneuploidy in rare developmental disorder

Cells duplicate their chromosomes before they divide. Then during cell division, the chromosomes are equally divided over the two new daughter cells; a process called chromosome segregation. When errors occur during this process, one daughter cell can end up with more chromosomes than the other. When cells have too many or too few copies of chromosomes, this is called aneuploidy. Aneuploidy is not only a hallmark of cancer; it is also common in a rare developmental disease called Mosaic Variegated Aneuploidy (MVA). Patients with this disorder can also suffer from various other symptoms, including developmental delays and brain defects. Some patients develop specific types of childhood cancer, such as leukemia.

Mutations in CENATAC

In a new publication in EMBO, researchers from the groups of Geert Kops and Mikko Frilander describe their study into the causes of aneuploidy. “We looked at the DNA of patients with MVA and found mutations in a gene called CENATAC. After further analyses, we discovered that CENATAC is a component of a protein machine known as the minor spliceosome,” says Bas de Wolf, first author on the paper. The minor spliceosome is important for the correct production of proteins.

Cause of aneuploidy

“We show that CENATAC, whose function was unknown before, plays a unique role in the minor spliceosome. Malfunction of this gene, for example due to a mutation, most likely affects the proteins that are important for correct chromosome segregation during cell division,” de Wolf explains. By this mechanism, errors occur during cell division, which can cause aneuploidy. Given that aneuploidy is commonly associated with human diseases such as cancer, studies like these are vital to further our understanding of the causes of aneuploidy.

Video: Due to CENATAC malfunction, this cell is unable to properly position its chromosomes (upper panel) in preparation for cell division. You can also see that after +- 7 hours the mitotic spindle (lower panel) starts falling apart. Credit: Bas de Wolf, copyright: Hubrecht Institute.

Publication

Bas de Wolf, Ali Oghabian, Maureen V Akinyi, Sandra Hanks, Eelco C Tromer, Jolien J E van Hooff, Lisa van Voorthuijsen, Laura E van Rooijen, Jens Verbeeren, Esther C H Uijttewaal, Marijke P A Baltissen, Shawn Yost, Philippe Piloquet, Michiel Vermeulen, Berend Snel, Bertrand Isidor, Nazneen Rahman, Mikko J Frilander, Geert J P L Kops. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC. EMBO, 2021.