Myotilin protein is expressed specifically in muscle and localizes to the myofiber Z-disc. Two independent missense mutations in the myotilin gene cause Limb-Girdle Muscular Dystrophy Type 1A (LGMD1A), and two separate myotitin missense single nucleotide polymorphisms (SNPs) show a positive association with dilated cardiomyopathy (DCM). The amino acid substitutions resulting from these mutations occur at the N-terminus of myotilin, a domain with no known function. To explore the effects of the LGMD1A mutations on myotilin and muscle function, I propose to perform immunohistochemistry on LGMD1A muscle, targeting myotilin, myotilin-interacting proteins, and additional proteins that localize to the myofiber Z-disc. I propose to construct three mutant myotilin transgenes and thoroughly characterize their effects on muscle function in transgenic mice. Such mice will also provide a wealth of tissue for downstream immunohistochemical and biochemical experiments. I will also characterize a novel myotilin isoform that is expressed predominantly in cardiac muscle, and continue to genotype myotilin SNPs in an expanding set of DCM patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS047910-04
Application #
7183516
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Porter, John D
Project Start
2004-04-03
Project End
2007-05-22
Budget Start
2007-04-03
Budget End
2007-05-22
Support Year
4
Fiscal Year
2007
Total Cost
$2,388
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Garvey, Sean M; Liu, Yutao; Miller, Sara E et al. (2008) Myotilin overexpression enhances myopathology in the LGMD1A mouse model. Muscle Nerve 37:663-7
Garvey, Sean M; Miller, Sara E; Claflin, Dennis R et al. (2006) Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM. Hum Mol Genet 15:2348-62