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ACTN2 encodes alpha-actinin-2, a structural protein expressed in both cardiac and skeletal muscle sarcomeres. The primary function of the protein is to cross-link actin in the sarcomere Z-disk. The gene has a long-standing association with cardiomyopathy, but recently, it has been shown to cause distal myopathy as well. Distal myopathies are a group of rare, inherited muscular disorders characterized by muscle weakness beginning in the lower arms and legs. Since the discovery of ACTN2 as a Distal myopathy gene, many new variants have been identified. However, with small number of patients and limited understanding of the underlying molecular mechanisms, variant interpretation is currently challenging. One of the few clearly demonstrated disease mechanisms of ACTN2 variants is aggregation of mutated protein. It is hypothesized that these aggregating proteins accumulate in muscle cells over time, causing late-onset Distal myopathy. Using a cellular model and over 100 GFP-tagged ACTN2 constructs, we screened for aggregating variants in various domains of the gene. We found nearly 20 positions with aggregating variants in the actin binding region, more specifically in the interface between its two calponin homology domains. Additionally, a few positions with aggregating variants were identified in the neck region of the protein. In contrast, no aggregating variants were found in the EF34-domain. These results suggest that the interface between the two calponin homology domains of the actin binding region is susceptible to aggregation causing variants. The results indicate that aggregation screening may be a useful initial test to assess the pathogenicity of variants of uncertain significance in the actin binding region of alpha-actinin-2. The screening experiment will be expanded to cover a larger fraction of the gene, which, together with further functional work characterizing other possible molecular disease mechanisms, will ease ACTN2 variant interpretation. [ABSTRACT FROM AUTHOR]

Purpose of Review: Distal myopathies are a clinically heterogenous group of rare, genetic muscle diseases, that present with weakness in hands and/or feet at onset. Some of these diseases remain accentuated in the distal muscles whereas others may later progress to the proximal muscles. In this review, the latest findings related to genetic and clinical features of distal myopathies are summarized., Recent Findings: Variants in SMPX , DNAJB2, and HSPB6 have been identified as a novel cause of late-onset distal myopathy and neuromyopathy. In oculopharyngodistal myopathies, repeat expansions were identified in two novel disease-causing genes, RILPL1 and ABCD3. In multisystem proteinopathies, variants in HNRNPA1 and TARDBP , genes previously associated with amyotrophic lateral sclerosis, have been shown to cause late-onset distal myopathy without ALS. In ACTN2 -related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present., Summary: The identification of novel distal myopathy genes and pathogenic variants contribute to our ability to provide a final molecular diagnosis to a larger number of patients and increase our overall understanding of distal myopathy genetics and pathology., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The objective of the study is to characterize the pathomechanisms underlying actininopathies. Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begin 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., Methods: Functional characterization in C2C12 cell model of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant and recessive actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants., 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 form alpha-actinin-2 aggregates., 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., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and skeletal muscle. The protein, located in the sarcomere Z-disk, functions as a link between the anti-parallel actin filaments. This important structural protein also binds N-terminal titins, and thus contributes to sarcomere stability. Previously, ACTN2 mutations have been solely associated with cardiomyopathy, without skeletal muscle disease. Recently, however, ACTN2 mutations have been associated with novel congenital and distal myopathy. Previously reported variants are in varying locations across the gene, but the potential clustering effect of pathogenic locations is not clearly understood. Further, the genotype-phenotype correlations of these variants remain unclear. Here we review the previously reported ACTN2-related molecular and clinical findings and present an additional variant, c.1840-2A>T, that further expands the mutation and phenotypic spectrum. Our results show a growing body of clinical, genetic, and functional evidence, which underlines the central role of ACTN2 in the muscle tissue and myopathy. However, limited segregation and functional data are available to support the pathogenicity of most previously reported missense variants and clear-cut genotype-phenotype correlations are currently only demonstrated for some ACTN2-related myopathies., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)