Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Poster Abstracts

6-POS Board 6 MISSENSE MUTATIONS IN THE CENTRAL PART OF CARDIAC MYBP-C AND THEIR POTENTIAL CONTRIBUTION TO HYPERTROPHIC CARDIOMYOPATHY Amy Pearce 1 ; Saraswathi Ponnam 2 ; Mark R Holt 1 ; Thomas Randall 1 ; Thomas Kampourakis 2 ; Elisabeth Ehler 1,2 ; 1 King's College London, School of Cardiovascular and Metabolic Medicine and Sciences, London, United Kingdom 2 King's College London, Randall Centre for Cell and Molecular Biophysics, London, United Kingdom Mutations in the MYBPC3 gene are amongst frequent causes for hypertrophic cardiomyopathy. In addition to truncating mutations, there also missense mutations were reported, which tend to be found in the central domains of the MyBP-C molecule. This suggests that these central domains are more than just a spacer between the better characterised N- and C-terminal domains. We have analysed the potential impact of four different missense mutations (E542Q; G596R; N755K; R820Q) that are spread over the domains C3 to C6 on the function of MyBP-C in vitro and in cardiomyocytes. Effect on domain stability, interaction with thin filaments, binding to myosin and subcellular localisation behaviour were assessed. Our studies show that these missense mutations result in slightly different phenotypes at the molecular level that are mutation specific, but that the expected functional readout of each mutation provides a valid explanation for an impaired contribution of MyBP-C to the regulation of muscle contraction.

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