The genetic architectures of cancer and congenital disorders are heterogeneous and incompletely mapped. Rare and low-frequency variants of incomplete penetrance are emerging as an important class of germline and somatic variation, but their contribution to disease remains poorly characterised. This thesis aims to identify and assess pathogenic mutations in the 1q41q42 microdeletion syndrome, neural tube defects, neuropsychiatric disorders and cancer. Rare microdeletions at the 1q41q42 locus cause a clinically heterogeneous syndrome characterized by developmental delay, characteristic dysmorphic features and brain morphological abnormalities. Examining new and published patients with 1q41q42 microdeletions, we found that TP53BP2, encoding ASPP2, is a strong candidate for being the gene responsible for brain morphological abnormalities of the syndrome. Mice deficient for Trp53bp2 show multiple abnormalities overlapping the features of the 1q41q42 microdeletion syndrome such as dysmorphic lateral ventricles, heart and urogenital abnormalities. ASPP2 deficiency also causes neural tube defects, hopping gait, and male-specific motion hyperactivity in mice. We further identify candidate pathogenic TP53BP2 duplications, implicating TP53BP2 dosage sensitivity in the ganglionic eminences of the developing brain, manifested by structural abnormalities in the striatum and lateral ventricles of both deletion and duplication patients. ASPP2 controls neuroepithelial cell polarity via Par3 and genetic disruption of aPKC-Par3 interaction by rare missense variants was implicated in human neural tube defects. An integrative analysis of cancer genomic data revealed that PPP1R13B, encoding ASPP1, bears many hallmarks of a tumour suppressor gene, despite being mutated at a low absolute frequency. A subset of missense somatic mutations in ASPP genes genetically interact with TP53 mutations, disrupting an autoinhibitory mechanism to modulate p53-dependent transcription. In summary, this work identified novel candidate pathogenic variants in developmental disorders and cancer, and explored the mechanisms underlying their respective genotype-phenotype links.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:729981 |
| Date | January 2016 |
| Creators | Zak, Jaroslav |
| Contributors | Lu, Xin ; Teijaro, John |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://ora.ox.ac.uk/objects/uuid:58844495-fca0-4090-8462-22e6f919f127 |
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