Human Molecular Genetics Advance Access originally published online on June 26, 2006
Human Molecular Genetics 2006 15(15):2348-2362; doi:10.1093/hmg/ddl160
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM
1 Center for Human Genetics, 2 University Program in Genetics and Genomics and 3 Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA and 4 Department of Surgery and 5 Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109-2007, USA
* To whom correspondence should be addressed at: Duke University Medical Center, DUMC Box 3445, Durham, NC 27710, USA. Tel: +1 9196843508; Fax: +1 9196840902; Email: mhauser{at}chg.duhs.duke.edu
Received April 26, 2006; Accepted June 21, 2006
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), 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 promoter. Similar to 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 muscle of transgenic mice exhibits significantly reduced maximum specific isometric force compared with 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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. J. Cohen, D. S. Waddell, T. Barrientos, Z. Lu, G. Feng, G. A. Cox, S. C. Bodine, and T.-P. Yao The Histone Deacetylase HDAC4 Connects Neural Activity to Muscle Transcriptional Reprogramming J. Biol. Chem., November 16, 2007; 282(46): 33752 - 33759. [Abstract] [Full Text] [PDF]
|
|