Tnnt1-flox Mouse

Tnnt1, encoding slow skeletal muscle troponin T, is one of three homologous genes in vertebrates that encode muscle type-specific troponin T isoforms. Troponin T (TnT) is crucial for the calcium regulation of actin thin filament function and essential for striated muscle contraction [2].

In terms of disease-related findings, TNNT1-related nemaline myopathies are clinically and genetically heterogeneous. For example, a 16-year-old Korean boy with progressive muscle weakness was found to have novel compound heterozygous mutations in TNNT1, and exon 11 skipping in the splicing variant was confirmed. The functional impact of the missense variant was verified using a zebrafish loss-of-function model [1]. Also, the 'Amish' nemaline myopathy, caused by a TNNT1 pathogenic mutation, is an infantile-onset, lethal disease. Affected children show progressive muscle weakness, atrophy, and respiratory failure. Similar phenotypes were observed in two transgenic murine models (Tnnt1-/-and Tnnt1 c.505G>T) [3]. A novel recessive congenital TNNT1 core-rod myopathy was reported in French Canadians. A zebrafish loss-of-function model was created to assess the pathogenicity of the identified variant, and wild-type TNNT1 mRNA could rescue the zebrafish morphants while mutant transcripts failed [4]. In a Chinese girl with TNNT1 nemaline myopathy, a splicing mutation led to exon skipping and both the truncation and splicing mutations triggered nonsense-mediated mRNA decay [5].

In conclusion, Tnnt1 is essential for normal skeletal muscle function. Studies using gene knockout or loss-of-function models, such as zebrafish and transgenic murine models, have significantly contributed to understanding TNNT1-related nemaline myopathies. These models help reveal the role of Tnnt1 in muscle development and function, providing insights into potential therapeutic strategies for these muscle-related disorders.