ACTA1, encoding skeletal muscle alpha-actin, forms the core of the sarcomeric thin filament in adult skeletal muscle. It is one of six highly conserved actin proteins associated with human disease [1].

Mutations in ACTA1 are a significant genetic cause of nemaline myopathy, with the vast majority (74%) of ACTA1 variants causing this disorder. However, an increasing number of variants are also linked to cardiomyopathy and novel phenotypes like distal myopathy [1]. In an in vitro model of nemaline myopathy using iPSC-derived skeletal myocytes with an ACTA1 H40Y point mutation, mitochondrial dysfunction and oxidative stress were observed as disease phenotypes, though nemaline rods were absent [2]. Clinically, the number of reported ACTA1-related disease phenotypes has grown from five to 20, and there seems to be a correlation between clinical/histological presentations and mutation positions in ACTA1-related nemaline myopathy [1,3].

In summary, ACTA1 is crucial for the normal assembly and function of the thin filament in skeletal muscle. Studies, including in vitro models, have revealed its role in muscle-related disorders such as nemaline myopathy and cardiomyopathy. Understanding ACTA1 through these research models is key to deciphering the mechanisms of these diseases and potentially developing targeted therapies.

References:

1. Clayton, Joshua S, Johari, Mridul, Taylor, Rhonda L, Ravenscroft, Gianina, Laing, Nigel G. 2024. An Update on Reported Variants in the Skeletal Muscle α-Actin (ACTA1) Gene. In Human mutation, 2024, 6496088. doi:10.1155/2024/6496088. https://pubmed.ncbi.nlm.nih.gov/40225930/

2. Gartz, Melanie, Haberman, Margaret, Sutton, Jessica, Mack, David L, Lawlor, Michael W. 2023. ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy. In Experimental cell research, 424, 113507. doi:10.1016/j.yexcr.2023.113507. https://pubmed.ncbi.nlm.nih.gov/36796746/

3. Moreno, Cristiane de Araújo Martins, Abath Neto, Osório, Donkervoort, Sandra, Bönnemann, Carsten, Zanoteli, Edmar. 2017. Clinical and Histologic Findings in ACTA1-Related Nemaline Myopathy: Case Series and Review of the Literature. In Pediatric neurology, 75, 11-16. doi:10.1016/j.pediatrneurol.2017.04.002. https://pubmed.ncbi.nlm.nih.gov/28780987/