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Telomere length and dynamics in Hutchinson-Gilford progeria syndrome

University of British Columbia

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in the gene LMNA, which encodes the nuclear matrix protein, Lamin A. Lamin A is found predominantly at the nuclear periphery but also throughout the nucleus in a ‘nucleoplasmic veil’. The majority of HGPS patients have a single nucleotide mutation (1824 C→T) which results in the activation of a cryptic donor splice site causing a 150 nucleotide deletion in the mRNA and consequently a 50 amino acid in-frame deletion in the protein. The mutation results in aberrant processing and nuclear localization of the Lamin A protein. HGPS cells are characterized by misshapen nuclei, chromatin disorganization, accumulation of mutant Lamin A, short telomeres, DNA damage recruitment defect and early senescence. To measure the telomere length of individual chromosomes, Quantitative Fluorescence in-situ Hybridization was used. The average telomere length in HGPS fibroblasts was greatly decreased compared to controls as well as highly variable. In contrast, the telomere length in hematopoietic cells which do not express LMNA was within the normal range for three out of four HGPS patient samples. These results suggest that mutant Lamin A decreases telomere length via a direct effect and that expression of mutant LMNA is necessary for telomere loss in HGPS. Three different aspects of telomere biology were investigated: localization, mobility and attachment to the matrix. Telomeres were more localized to the nuclear periphery in HGPS fibroblasts than in wild type fibroblasts as well as having abnormal localization in regards to euchromatin/heterochromatin. To examine mobility, fluorescently tagged proteins were constructed to examine interactions between wild type and mutant Lamin A and telomeres during live cell imaging. Long telomeres in cells with the mutant protein did not move the same distance as those in wild type cells. Mutant Lamin A did not bind DNA with the same affinity as the wild type Lamin A did. These investigations show that telomeres and telomere dynamics are altered in HGPS cells. This is likely contributing to aspects of the pathology of the disease and would need to be taken into consideration in any therapeutic approach.

Text

2011-05-02

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/34180

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/