Human Molecular Genetics Advance Access originally published online on November 25, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 2 181-190
DOI: 10.1093/hmg/ddh017
Myopathy phenotype in transgenic mice expressing mutated PABPN1 as a model of oculopharyngeal muscular dystrophy
1Department of Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 862-0976, Japan, 2Department of Neurology Advanced Biomedical Sciences, Faculty of Medical and Pharmaceutical Sciences, Graduate School of Medical Science, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan, 3Department of Cell Pathology, Kumamoto University School of Medicine, Kumamoto, 860-0811, Japan and 4Department of Bioinformatics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
Received August 26, 2003; Revised October 30, 2003; Accepted November 9, 2003
Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized clinically by progressive ptosis, dysphagia and limb weakness, and by unique intranuclear inclusions in the skeletal muscle fibers. The disease is caused by the expansion of a 10-alanine stretch to 12–17 alanine residues in the poly(A)-binding protein, nuclear 1 (PABPN1; PABP2). While PABPN1 is a major component of the inclusions in OPMD, the exact cause of the disease is unknown. To elucidate the molecular mechanism and to construct a useful model for therapeutic trials, we have generated transgenic mice expressing the hPABPN1. Transgenic mice lines expressing a normal hPABPN1 with 10-alanine stretch did not reveal myopathic changes, whereas lines expressing high levels of expanded hPABPN1 with a 13-alanine stretch showed an apparent myopathy phenotype, especially in old age. Pathological studies in the latter mice disclosed intranuclear inclusions consisting of aggregated mutant hPABPN1 product. Furthermore, some TUNEL positive nuclei were shown around degenerating fibers and a cluster of it in the lesion in necrotic muscle fibers. Interestingly, the degree of myopathic changes was more prominent in the eyelid and pharyngeal muscles. Further, muscle weakness in the limbs was apparent as shown by the fatigability test. Nuclear inclusions seemed to develop gradually with aging, at least after 1 week of age, in model mouse muscles. We established the first transgenic mouse model of OPMD by expressing mutated PABPN1, and our model mice appear to have more dramatic alternations in myofiber viability.
* To whom correspondence should be addressed. Tel: +81 963736083; Fax: +81 963736599; Email: yamamura{at}gpo.kumamoto-u.ac.jp
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