Mosaic Variegated Aneuploidy. Elucidating the molecular causes of constitutional aneuploidy in humans

Abstract

Mosaic Variegated Aneuploidy (MVA) is a rare developmental disorder characterized by a clinically heterogeneous phenotype and the presence of mosaic aneuploidies (predominantly trisomies and monosomies of mostly random chromosomes). These aneuploid cells are most likely the result of chromosome segregation errors in mitosis, as disease-causing mutations were found in the mitotic genes BUB1B and CEP57. Although several theories have been proposed, it is currently unclear what is the molecular mechanism of pathogenicity underlying MVA and whether the presence of aneuploid cells contributes to it. The aim of this thesis was to investigate the molecular causes of aneuploidy in MVA and to uncover MVA’s underlying pathogenic mechanism. We first summarized the current knowledge about the processes governing mitosis and about the disorders that are associated with mutations in kinetochore genes (chapter 2). In the subsequent chapters, we presented clinical case studies of MVA patients in which we identified disease-causing mutations in mitotic regulators (TRIP13, CENATAC, KNL1, and ZWINT), and our findings concerning the molecular causes of CIN and aneuploidy in these patients (chapters 3/4/5). In chapter 3, we showed that patient mutations in both BUB1B and TRIP13 led to a severe impairment of the spindle assembly checkpoint (SAC) and that there is a strikingly strong correlation between mutations in these two genes and the occurrence of specific childhood cancers in MVA patients. Moreover, all patients with mutations in TRIP13 had developed Wilms tumors, and we subsequently identified non-MVA patients with Wilms tumors that also had germline TRIP13 mutations. TRIP13 may therefore be a Wilms tumor suppressor gene. In chapter 4, we identified CENATAC as a novel component of the minor spliceosome and showed that CENATAC depletion led to missplicing of a newly identified minor intron subtype, which in turn caused a chromosome congression defect in mitosis. In chapter 5, we showed that patient mutations in KNL1 weakened the SAC and reduced the kinetochore localization of several key mitotic regulators. Based on these and other findings, I here discuss the different theories regarding the molecular mechanism of pathogenicity underlying MVA, and reveal that the current requirements for MVA’s diagnosis are most likely incompatible with its disease-causing mechanism. In addition, I summarize cancer incidence in both MVA and MVA-like patients with mosaic aneuploidies, and I discuss the potential contribution of aneuploidy to the development of cancer in these patients. I conclude by comparing MVA to similar developmental disorders and discuss why it may be necessary to re-define MVA.