Browsing by Author "Ranta-aho, Johanna"

Distal myopathies are a group of inherited diseases that cause progressive muscle weakness primarily in the hands and feet. Variants in various different genes have been identified as disease-causing, but most recently, variants in ACTN2, a gene previously associated with cardiomyopathy, have been shown to cause a distal myopathy phenotype. ACTN2 encodes alpha-actinin-2, an important structural protein that links actin and titin to the sarcomere Z-disk. In ACTN2-related diseases, actininopathies, several variants have been identified as disease-causing, however, new variants are continuously discovered, and the significance of many variants remain unknown. Thus, lack of clear genotype-phenotype correlations in actininopathies persists. Further, the molecular mechanisms underlying actininopathies are largely unknown, especially in recessive actininopathies. Here, a reanalysis of the previously reported ACTN2-related molecular and clinical findings is conducted, with a subsequent reclassification of variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. The results indicate that ACTN2 serves an important function in the muscle tissue and is involved in the pathomechanisms of myopathy, which is supported by a growing body of clinical, genetic, and functional evidence. However, distinct genotype-phenotype correlations are currently clearly understood only in some actininopathies, and limited segregation and functional data are still available to support the pathogenicity of most previously reported missense variants. Additionally, functional characterization of ACTN2 variants identified in recessive actininopathies suggest that the underlying molecular mechanisms of recessive actininopathies are different form the dominant from of the disease, as they do not produce detectable alpha-actinin-2 aggregates in the cell models. Thus, alternate methods should be used to investigate the molecular mechanisms of recessive actininopathies. Also, the results suggest that multiple different molecular mechanisms are involved in dominant actininopathies.