Journal article
Ovine congenital progressive muscular dystrophy (OCPMD) is a model of TNNT1 congenital myopathy
Acta Neuropathologica Communications, Vol.8(1), Art. 142
2020
Abstract
Ovine congenital progressive muscular dystrophy (OCPMD) was first described in Merino sheep flocks in Queensland and Western Australia in the 1960s and 1970s. The most prominent feature of the disease is a distinctive gait with stiffness of the hind limbs that can be seen as early as 3 weeks after birth. The disease is progressive. Histopathological examination had revealed dystrophic changes specifically in type I (slow) myofibres, while electron microscopy had demonstrated abundant nemaline bodies. Therefore, it was never certain whether the disease was a dystrophy or a congenital myopathy with dystrophic features. In this study, we performed whole genome sequencing of OCPMD sheep and identified a single base deletion at the splice donor site (+ 1) of intron 13 in the type I myofibre-specific TNNT1 gene (KT218690 c.614 + 1delG). All affected sheep were homozygous for this variant. Examination of TNNT1 splicing by RT-PCR showed intron retention and premature termination, which disrupts the highly conserved 14 amino acid C-terminus. The variant did not reduce TNNT1 protein levels or affect its localization but impaired its ability to modulate muscle contraction in response to Ca2+ levels. Identification of the causative variant in TNNT1 finally clarifies that the OCPMD sheep is in fact a large animal model of TNNT1 congenital myopathy. This model could now be used for testing molecular or gene therapies.
Details
- Title
- Ovine congenital progressive muscular dystrophy (OCPMD) is a model of TNNT1 congenital myopathy
- Authors/Creators
- J.S. Clayton (Author/Creator) - Harry Perkins Institute of Medical ResearchE.L. McNamara (Author/Creator) - Harry Perkins Institute of Medical ResearchH. Goullee (Author/Creator) - Queen Elizabeth II Medical CentreS. Conijn (Author/Creator) - Department of Physiology, Amsterdam University Medical Center (Location VUmc), Amsterdam, NetherlandsK. Muthsam (Author/Creator) - The University of Western AustraliaG.C. Musk (Author/Creator) - The University of Western AustraliaD. Coote (Author/Creator) - Queen Elizabeth II Medical CentreJ. Kijas (Author/Creator) - Commonwealth Scientific and Industrial Research OrganisationA.C. Testa (Author/Creator) - Harry Perkins Institute of Medical ResearchR.L. Taylor (Author/Creator) - Harry Perkins Institute of Medical ResearchA.J. O’Hara (Author/Creator)D. Groth (Author/Creator) - Curtin UniversityC. Ottenheijm (Author/Creator)G. Ravenscroft (Author/Creator) - Queen Elizabeth II Medical CentreN.G. Laing (Author/Creator) - Queen Elizabeth II Medical CentreK.J. Nowak (Author/Creator) - Harry Perkins Institute of Medical Research
- Publication Details
- Acta Neuropathologica Communications, Vol.8(1), Art. 142
- Publisher
- BioMed Central
- Identifiers
- 991005545028107891
- Copyright
- © 2020 The Authors
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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