Folkhälsan Research Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
Department of Medical Genetics, Medicum, University of Helsinki, Haartmaninkatu 8, Helsinki, 00290, Finland.
Ann Clin Transl Neurol. 2024 Sep;11(9):2392-2405. doi: 10.1002/acn3.52154. Epub 2024 Aug 2.
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.
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.
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.
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.
本研究旨在探讨肌动蛋白病的发病机制。远端肌病是一组罕见的遗传性肌肉疾病，其特征是手臂和腿部远端的肌肉纤维进行性丧失。最近，一种新的疾病基因 ACTN2 的变异被证明可导致远端肌病。ACTN2 以前仅与心肌病相关，其编码的α-辅肌动蛋白-2 是一种在心肌和骨骼肌肌节中均有表达的蛋白质。α-辅肌动蛋白-2 的主要功能是将肌动蛋白和titin 连接到肌节 Z 盘上。新的 ACTN2 变异不断被发现；然而，许多变异的临床意义仍然未知。因此，在 ACTN2 相关疾病——肌动蛋白病中，仍然缺乏明确的基因型-表型相关性。
在 C2C12 细胞模型中对几种 ACTN2 变异进行功能特征分析，包括与显性和隐性肌动蛋白病相关的移码和错义变异。我们使用携带这些变异的几位患者的临床数据评估肌动蛋白病的基因型-表型相关性。
结果表明，与隐性肌动蛋白病相关的错义变异不会在细胞模型中引起可检测到的α-辅肌动蛋白-2 聚集。相反，导致蛋白质延伸的显性移码变异确实会形成α-辅肌动蛋白-2 聚集。
结果表明，α-辅肌动蛋白-2 聚集是一些显性肌动蛋白病的发病机制，因此，我们建议将 ACTN2 中的蛋白延伸移码变异归类为致病性变异。然而，这种机制可能仅由有限数量的变异引起。应该探索替代的功能特征分析方法，以进一步研究肌动蛋白病的其他分子机制。
