Synemin-related skeletal and cardiac myopathies: an overview of pathogenic variants.

ABSTRACT

This review analyzes data concerning patients with cardiomyopathies or skeletal myopathies associated with a variation in the intermediate filament (IF) synemin gene (SYNM), also referred to as desmuslin (DMN). Molecular studies demonstrate that synemin copolymerizes with desmin and vimentin IF and interacts with vinculin, α-actinin, α-dystrobrevin, dystrophin, talin, and zyxin. It has been found that synemin is an A-kinase-anchoring protein (AKAP) that anchors protein kinase A (PKA) and modulates the PKA-dependent phosphorylation of several cytoskeletal substrates such as desmin. Because several IF proteins, including desmin, have been implicated in human genetic disorders such as dominant or recessive congenital and adult-onset myopathy, synemin becomes a significant candidate for cardiac and skeletal myopathies of unknown etiology. Because SYNM is a new candidate gene that displays numerous sequence polymorphisms, in this review, we summarize the genetic and clinical literature about SYNM mutations. Protein-changing variants (missense, frameshifts, nonsense) were further evaluated based on structural modifications and amino acid interactions. We present in silico modeling of helical salt-bridges between residues to evaluate the impact of the synemin networks crucial to interactions with cytoskeletal proteins. Finally, a discussion is featured regarding certain variants that may contribute to the disease state.