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Protein haploinsufficiency drivers identify MYBPC3 mutations that cause hypertrophic cardiomyopathy

Carmen Suay-Corredera, Maria Rosaria Pricolo, Elias Herrero-Galan, Diana Velazquez-Carreras, David Sanchez-Ortiz, Diego Garcia-Giustiniani, Javier Delgado, Juan Jose Galano-Frutos, Helena Garcia-Cebollada, Silvia Vilches, Fernando Dominguez, Maria Sabater Molina, Roberto Barriales-Villa, Giulia Frisso, Javier Sancho, Luis Serrano, Pablo Garcia-Pavia, Lorenzo Monserrat, Jorge Alegre-Cebollada.

Abstract: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Mutations in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are a leading cause of HCM. However, it remains challenging to define whether specific gene variants found in patients are pathogenic or not, limiting the reach of cardiovascular genetics in the management of HCM. Here, we have examined cMyBP-C haploinsufficiency drivers in 68 clinically annotated non-truncating variants of MYBPC3. We find that 45% of the pathogenic variants show alterations in RNA splicing or protein stability, which can be linked to pathogenicity with 100% and 94% specificity, respectively. Relevant for variant annotation, we uncover that 9% of non-truncating variants of MYBPC3 currently classified as of uncertain significance induce one of these molecular phenotypes. We propose that alteration of RNA splicing or protein stability caused by MYBPC3 variants provide strong evidence of their pathogenicity, leading to improved clinical management of HCM patients and their families.

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Nanorheology of living cells measured by AFM-based force–distance curves

Pablo D. Garcia, Carlos R. Guerrero and Ricardo Garcia

Abstract: Mechanobiology aims to establish functional relationships between the mechanical state of a living a cell
and its physiology. The acquisition of force–distance curves with an AFM is by far the dominant method to characterize the nanomechanical properties of living cells. However, theoretical simulations have shown that the contact mechanics models used to determine the Young’s modulus from a force–distance curve could be off by a factor 5 from its expected value. The semi-quantitative character arises from the lack of a theory that integrates the AFM data, a realistic viscoelastic model of a cell and its finitethickness. Here, we develop a method to determine the mechanical response of a cell from a force–distance curve. The method incorporates bottom-effect corrections, a power-law rheology model and the deformation history of the cell. It transforms the experimental data into viscoelastic parameters of the cell as a function of the indentation frequency. The quantitative agreement obtained between the experiments performed on living fibroblast cells and the analytical theory supports the use of force–distance curves to measure the nanorheological properties of cells.

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