CONGENITAL MYOPATHIES 1 – NEMALINE

Ovine congenital progressive muscular dystrophy (OCPMD) was first described in Merino sheep flocks in Queensland and Western Australia (WA) in the 1960s and 70s. The most prominent feature of the disease is a distinctive gait with stiffness of the hind limbs that can be seen as early as three weeks after birth. The disease is progressive. Histopathological examination had revealed dystrophic changes specifically in slow myofibres, while electron microscopy had demonstrated abundant nemaline bodies. Therefore, it was never certain whether the disease was a dystrophy or a nemaline myopathy with dystrophic features. In this study, we performed whole genome sequencing of WA OCPMD sheep and identified a single base deletion at the splice donor site (+1) of intron 13 of the slow 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 WA OCPMD sheep is in fact a large animal model of nemaline myopathy with dystrophic features. This model could now be used for testing molecular or gene therapies.