Document Type

Thesis

Date of Degree

Summer 2012

Degree Name

MS (Master of Science)

Degree In

Biochemistry

First Advisor

Lori L. Wallrath

Second Advisor

Peter A. Rubenstien

Abstract

Mutations in the human LMNA gene encoding A-type lamins cause a collection of diseases termed laminopathies, including several types of muscular dystrophy. Lamins are intermediate filaments, which line the inner membrane of nuclear envelope. Lamins maintain the nuclear shape and regulate gene expression through interactions with chromatin. Heterozygous mutations LMNA, which result in single amino acid substitutions within the C-terminal Ig-fold domain, were identified in patients with muscular dystrophy. These substitutions were modeled in Drosophila and found to cause muscle defects. We have taken a multi-disciplinary approach to understanding the molecular basis of these muscle defects. Using Nuclear Magentic Resonance (NMR) and Circular Dischroism (CD) we determined that the amino acid substitutions cause perturbations of the tertiary, but not secondary, structure of the Ig-fold. Microarray analysis of RNA isolated from muscle revealed that mutant lamins cause cause mis-regulation of genes involved oxidative stress and neuromuscular junction function. Collectively, these data demonstrate that perturbations within the lamin Ig-fold cause changes in gene expression, providing insights on pathways involved in pathogenesis and identifying new potential therapeutic targets.

Keywords

Microarray, NMR, Protein Purification, Research, Structural work

Pages

xi, 92 pages

Bibliography

Includes bibliographical references (page 89).

Comments

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Copyright

Copyright 2012 Om Kumar Shrestha

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Biochemistry Commons

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