Thesis defense Bas de Wolf: “Mosaic Variegated Aneuploidy”

Mosaic Variegated Aneuploidy (MVA) is a rare developmental disorder. Patients with MVA can suffer from a wide variety of symptoms, including mild dysmorphisms and developmental delays. Additionally, some patients develop specific types of childhood cancer, such as leukemia. The disease is characterized by aneuploidy: the presence of cells that have too many or too few copies of some chromosomes.

Aneuploidy

Aneuploidy is most likely caused by errors during cell division – also called mitosis. During the cell cycle, a cell duplicates its chromosomes, after which the chromosomes are equally divided over two new daughter cells. When errors occur during this process, one daughter cell can end up with more chromosomes than the other. When this happens, we speak of aneuploidy. Although MVA is characterized by the presence of many aneuploid cells, the underlying mechanism of the disease and the role of aneuploidy in this were still unclear. During his PhD, De Wolf therefore researched the molecular causes of MVA and how these lead to the development of the disease.

Discovery of mutations

Together with his colleagues, De Wolf made several discoveries. The researchers used so-called sequencing technology to look at the DNA of patients with MVA and found that they have mutations in four DNA regions. These regions are concerned with the process of cell division. Subsequently, De Wolf and his colleagues investigated what goes wrong during cell division in each of these patients. They identified several errors in this process that lead to aneuploidy and MVA. For example, the mutations in two of the identified regions weaken an important control mechanism for cell division: the mitotic checkpoint. The mitotic checkpoint verifies whether the duplicated chromosomes are accurately divided over the new daughter cells. By weakening this checkpoint, the mutations cause errors in cell division, which results in aneuploidy.

Errors

Once the four regions in the DNA were identified by de Wolf and his colleagues, they discovered that the function of a gene in one of these regions was still unknown. Additional investigation by the researchers showed that the gene is part of the minor spliceosome: a large protein that plays a pivotal role in the activation of genes. Mutations in this specific gene cause defects in the process of gene (de)activation, subsequently causing errors in chromosome segregation during cell division. Again, this results in aneuploidy.

Cell death

With his research, De Wolf shows the underlying causes of aneuploidy in patients with MVA. However, he also concludes that the presence of aneuploid cells is not sufficient nor required to cause MVA. Rather, he theorizes that cell death resulting from errors during cell division leads to the disease. De Wolf’s research contributes to our understanding of the causes of aneuploidy and the cellular mechanisms underlying MVA.