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UBC Theses and Dissertations

Genetic modifiers of telomere maintenance and their contributions to phenotypic variations in telomere biology disorders Xu, Jialin


Telomeres, the protective caps at the end of human chromosomes, are shortened during cellular proliferation in normal aging. Telomere biology disorders (TBDs) refer to a spectrum of tissue degenerative disorders caused by accelerated shortening of telomeres secondary to genetic defects in telomere biology genes. Defects in eleven genes involved in telomere length maintenance have been found to cause TBDs. Accelerated telomere shortening leads to premature aging at the cellular level and regenerative defects at the tissue level. TBD-related genetic defects, in concert with intrinsic tissue turn-over rate and various environmental insults that precipitate telomere shortening, determine the aging process of specific tissues and the clinical presentations of TBDs. The main objective of this dissertation is to investigate the genetic factors that contribute to phenotypic variations of TBDs. The thesis is divided into two sections based on the presentations of TBDs in fast- and slow-turnover tissues. In Chapter 2, using patient-derived cell models and DNA samples, I comprehensively assessed the molecular and cellular phenotypes of X-linked dyskeratosis congenita (X-DC) in female DKC1 mutation carriers. I demonstrated that successful X chromosome inactivation (XCI) in their blood cells led to normal dyskerin expression and function and thus normal telomere length maintenance. These populations should be free of hematopoietic disease manifestations. In contrast, protection from XCI in tissue compartments other than the hematopoietic system may not be complete, and DC manifestations could be observed in a patient-specific manner depending on the sum total of the environmental and inherited telomere lengths as confounding factors. Extending from the observation with phenotypic variations in female DKC1 mutation carriers, I further investigated how incomplete genetic perturbations of telomerase activity may impact clinical presentations of a common disease. In Chapter 3, using a combination of cell and clinical disease models, I showed that functional defects in telomerase catalytic activity, caused by selected genetic polymorphisms in TERT, led to suboptimal telomere length maintenance. Rapid progression of chronic obstructive pulmonary diseases is associated with patients’ carrying status of the minor allele of rs61748181. Collectively, my study revealed two genetic modifiers for potential causes of phenotypic variations in TBDs.

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