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.

• Authors: Denise Paulin, Yeranuhi Hovhannisyan, Serdar Kasakyan, Onnik Agbulut, Zhenlin Li, Zhigang Xue
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 318 Issue 4 Pg. C709-C718 (04 01 2020) ISSN: 1522-1563 [Electronic] United States
• PMID: 32023076 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Intermediate Filament Proteins
• Muscle Proteins
• desmuslin

Topics

• Animals
• Cytoskeleton (metabolism, pathology)
• Heart (physiopathology)
• Humans
• Intermediate Filament Proteins (metabolism)
• Intermediate Filaments (metabolism)
• Muscle Proteins (metabolism)
• Muscular Diseases (metabolism, pathology)