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.
| 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 |
