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A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy. | LitMetric

AI Article Synopsis

  • - A genetic variant in a specific gene was linked to a higher risk of heart disease, particularly cardiomyopathy, by influencing heart muscle cell structure (sarcomere).
  • - Researchers created genetically altered mice to explore the effects of this variant, finding that the associated Flii protein plays a crucial role in maintaining the length of actin thin filaments in heart muscle cells.
  • - The study suggests that this variant could lead to heart disease by disrupting normal sarcomere function and contractile dynamics, similar to other genetic heart conditions.

Article Abstract

To better understand the genetic basis of heart disease, we identified a variant in the () gene that generates a R1243H missense change and predisposes to cardiac remodeling across multiple previous human genome-wide association studies (GWAS). Since this gene is of unknown function in the mammalian heart we generated gain- and loss-of-function genetically altered mice, as well as knock-in mice with the syntenic R1245H amino acid substitution, which showed that Flii protein binds the sarcomeric actin thin filament and influences its length. Deletion of from the heart, or mice with the R1245H amino acid substitution, show cardiomyopathy due to shortening of the actin thin filaments. Mechanistically, Flii is a known actin binding protein that we show associates with tropomodulin-1 (TMOD1) to regulate sarcomere thin filament length. Indeed, overexpression of leiomodin-2 in the heart, which lengthens the actin-containing thin filaments, partially rescued disease due to heart-specific deletion of . Collectively, the identified human variant likely increases cardiomyopathy risk through an alteration in sarcomere structure and associated contractile dynamics, like other sarcomere gene-based familial cardiomyopathies.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175844PMC
http://dx.doi.org/10.1073/pnas.2213696120DOI Listing

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