CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.229Genetics and modeling of TNNT1 genetic variants in nemaline myopathy

Abstract

TNNT1-related nemaline myopathy (NEM5) comprises a small but increasingly significant cause of nemaline myopathy. Initially described as a severe autosomal recessive condition confined to the Old Order Amish of Pennsylvania in the US, subsequent patients with severe phenotypes have been described throughout the world. The prototypic clinical features include congenital hypotonia and weakness of proximal, bulbar, facial, and neck flexor muscles that may result in death secondary to respiratory insufficiency. This condition appears to exhibit allelic heterogeneity with multiple mutations within the same gene causing the severe recessive form of the disease. We recently described the first autosomal dominant c.311A>T, p.E104V pathogenic variant of TNNT1 gene occurring in an Ashkenazi Jewish family in the United States. This family had an overall milder phenotype than the recessive cases with marked clinical heterogeneity ranging from a Gower's maneuver in childhood to mild difficulty weight training late into adulthood. Recent whole exome sequencing studies in a large cohort of congenital myopathy cases have identified two additional unrelated cases with potentially pathogenic dominant TNNT1 mutations as well as two new instances of possible recessive variants. To assess pathogenicity of these variants we are establishing zebrafish models of both dominant gain of function and recessive loss of function for this gene. Morpholino-based knock down studies lead to significant neuromuscular abnormalities, including poor swimming ability, truncal curvature, and loss of birefringence, all indicative of defective muscle structure and function within the first week of life. Studies to model the dominant variants are in progress.