Date of Degree
2012
Document Type
thesis
Degree Name
MS (Master of Science)
Department
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.
Pages
xi, 92
Bibliography
89
Copyright
Copyright 2012 Om Kumar Shrestha
Recommended Citation
Shrestha, Om Kumar. "The effect of LMNA mutations on the lamin IG-fold structure and muscle gene expression." thesis, University of Iowa, 2012.
http://ir.uiowa.edu/etd/3383.
Comments
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