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Rare ACTN2 Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation.
- Source :
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MedRxiv : the preprint server for health sciences [medRxiv] 2024 Jan 17. Date of Electronic Publication: 2024 Jan 17. - Publication Year :
- 2024
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Abstract
- Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene, ACTN2 , have been shown to cause distal myopathy. ACTN2 , a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. New ACTN2 variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations in ACTN2 -related diseases, actininopathies, persists.<br />Objective: The objective of the study is to characterize the pathomechanisms underlying actininopathies.<br />Methods: Functional characterization in C2C12 cell models of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants.<br />Results: The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates.<br />Interpretation: The results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants in ACTN2 should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.
Details
- Language :
- English
- Database :
- MEDLINE
- Journal :
- MedRxiv : the preprint server for health sciences
- Accession number :
- 38293186
- Full Text :
- https://doi.org/10.1101/2024.01.17.23298671