Human Molecular Genetics Advance Access published online on June 26, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl160
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1 Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710; University Program in Genetics and Genomics, Duke University Medical Center, Durham, North Carolina, 27710
* To whom correspondence should be addressed. Myotilin is a muscle-specific Z-disc protein with putative roles in myofibril assembly and structural upkeep of the sarcomere. Several myotilin point mutations have been described in patients with Limb-Girdle Muscular Dystrophy Type 1A (LGMD1A), myofibrillar myopathy (MFM), and spheroid body myopathy (SBM), three similar adult-onset, progressive, and autosomal dominant muscular dystrophies. To further investigate myotilin's role in the pathogenesis of these muscle diseases, we have characterized three independent lines of transgenic mice expressing mutant (T57I) myotilin under the control of the human skeletal actin (HSA) promoter. Like LGMD1A and MFM patients, these mice develop progressive myofibrillar pathology that includes Z-disc streaming, excess myofibrillar vacuolization, and plaque-like myofibrillar aggregation. These aggregates become progressively larger and more numerous with age. We show that the mutant myotilin protein properly localizes to the Z-disc, and also heavily populates the aggregates, along with several other Z-disc associated proteins. Whole muscle physiological analysis reveals that the extensor digitorum longus (EDL) muscle of transgenic mice exhibits significantly reduced maximum specific isometric force compared to littermate controls. Intriguingly, the soleus and diaphragm muscles are spared of any abnormal myopathology and show no reductions in maximum specific force. These data provide evidence that myotilin mutations promote aggregate-dependent contractile dysfunction. In sum, we have established a promising patho-physiological mouse model that unifies the phenotypes of LGMD1A, MFM, and SBM.
Received April 26, 2006
Revised June 21, 2006
Accepted June 21, 2006
Article
Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM
Sean M. Garvey 1,
Sara E. Miller 2,
Dennis R. Claflin 3,
John A. Faulkner 3,
and
Michael A. Hauser 4 *
2 Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710
3 Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109-2007
4 Center for Human Genetics, Duke University Medical Center, DUMC Box 3445, Durham, North Carolina 27710; University Program in Genetics and Genomics, Duke University Medical Center, Durham, North Carolina, 27710
Michael A. Hauser, E-mail: mhauser{at}chg.duhs.duke.edu
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