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Mouse models of dominant ACTA1 disease recapitulate human disease and provide insight into therapies
Gianina Ravenscroft1, Connie Jackaman, Scott Bringans
1Centre for Medical Research, The University of Western Australia, Western Australian Institute for Medical Research, Nedlands, Australia. gina.ravenscroft@uwa.edu.au
Abstract:
Mutations in the skeletal muscle α-actin gene (ACTA1) cause a range of pathologically defined congenital myopathies. Most patients have dominant mutations and experience severe skeletal muscle weakness, dying within one year of birth. To determine mutant ACTA1 pathobiology, transgenic mice expressing ACTA1(D286G) were created. These Tg(ACTA1)(D286G) mice were less active than wild-type individuals. Their skeletal muscles were significantly weaker by in vitro analyses and showed various pathological lesions reminiscent of human patients, however they had a normal lifespan. Mass spectrometry revealed skeletal muscles from Tg(ACTA1)(D286G) mice contained ∼25% ACTA1(D286G) protein. Tg(ACTA1)(D286G) mice were crossed with hemizygous Acta1(+/-) knock-out mice to generate Tg(ACTA1)(D286G)(+/+).Acta1(+/-) offspring that were homozygous for the transgene and hemizygous for the endogenous skeletal muscle α-actin gene. Akin to most human patients, skeletal muscles from these offspring contained approximately equal proportions of ACTA1(D286G) and wild-type actin. Strikingly, the majority of these mice presented with severe immobility between postnatal Days 8 and 17, requiring euthanasia. Their skeletal muscles contained extensive structural abnormalities as identified in severely affected human patients, including nemaline bodies, actin accumulations and widespread sarcomeric disarray. Therefore we have created valuable mouse models, one of mild dominant ACTA1 disease [Tg(ACTA1)(D286G)], and the other of severe disease, with a dramatically shortened lifespan [Tg(ACTA1)(D286G)(+/+).Acta1(+/-)]. The correlation between mutant ACTA1 protein load and disease severity parallels effects in ACTA1 families and suggests altering this ratio in patient muscle may be a therapy for patients with dominant ACTA1 disease. Furthermore, ringbinden fibres were observed in these mouse models. The presence of such features suggests that perhaps patients with ringbinden of unknown genetic origin should be considered for ACTA1 mutation screening. This is the first experimental, as opposed to observational, evidence that mutant protein load determines the severity of ACTA1 disease.
Insights
Mutations in the skeletal muscle α-actin gene (ACTA1) cause congenital myopathies. Mouse models reveal that increased mutant ACTA1 protein load correlates with disease severity, suggesting a therapeutic target for dominant ACTA1-related muscle diseases.
Area of Science:
- Genetics
- Molecular Biology
- Pathology
Background:
- Mutations in the skeletal muscle α-actin gene (ACTA1) lead to congenital myopathies, often causing severe weakness and early mortality in patients.
- Dominant ACTA1 mutations are a significant cause of severe congenital myopathies.
Purpose of the Study:
- To investigate the pathobiology of mutant ACTA1 and establish relevant mouse models for ACTA1-related congenital myopathies.
- To correlate mutant ACTA1 protein levels with disease severity and identify potential therapeutic strategies.
Main Methods:
- Generation of transgenic mice expressing ACTA1(D286G) to model mild dominant ACTA1 disease.
- Crossbreeding transgenic mice with ACTA1 knock-out mice to create a severe disease model with a shortened lifespan.
- Skeletal muscle analysis using in vitro assays, mass spectrometry, and histological examination.
Main Results:
- Transgenic mice expressing ACTA1(D286G) exhibited muscle weakness and pathological lesions, with a normal lifespan.
- Mice with higher proportions of mutant ACTA1 protein showed severe immobility, shortened lifespan, and extensive muscle abnormalities, including nemaline bodies and sarcomeric disarray.
- A direct correlation was observed between mutant ACTA1 protein load and disease severity, mirroring human patient outcomes.
Conclusions:
- Established mouse models effectively recapitulate mild and severe forms of ACTA1-related congenital myopathies.
- Mutant protein load is a critical determinant of disease severity in dominant ACTA1 myopathies.
- Targeting the ratio of mutant to wild-type ACTA1 protein may offer a therapeutic approach for patients with dominant ACTA1 disease.
- The presence of ringbinden fibers in models suggests ACTA1 mutation screening for patients with unexplained ringbinden.
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