Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Medical Research Council (MR/V009540/1), Wellcome Trust (201543/B/16/Z) British Heart Foundation (FS/12/40/29712). Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition associated with diastolic dysfunction and sudden cardiac death. Disease genes for HCM are traditionally coding for proteins involved in force generation. More recently, it has emerged that variants in genes coding for proteins involved in biomechanical stress-signalling can also cause HCM. One such protein is filamin C, with proposed mechano-sensing functions in the heart. Within the protein, the immunoglobulin-like domain 20 (Ig20) may play a crucial role in mediating binding to muscle specific ligands. While the mechano-sensing functions of filamin C have been investigated well in skeletal muscle, the underlying cardiac disease mechanisms are not completely understood. Aim This work attempts to provide insights into the role of filamin C in cardiac mechano-sensing and dissect disease pathways leading to HCM in the presence of the FLNC variants in Ig20. Methods Using mass spectrometry, we aimed to provide a detailed analysis of the proteome of mice carrying the filamin C variant, using ventricular tissue samples from 14wk old homozygous mice. Samples were subject to molecular biology technical and underwent subcellular fractionation (n = 6 per genotype) and were investigated by label-free mass spectrometry. Results Utilising whole genome sequencing, a heterozygous FLNC missense variant in Ig20 was identified in a three-generation family affected by HCM. Mice carrying this variant recapitulate molecular features of HCM in the homozygous setting. Three proteins (FLNC, MYH7, MYOT) were found to be upregulated in the myofilament-enriched fraction. Up-regulations of key proteins were found to relocalise towards load-baring sites. Conclusion Our data indicate that changes in filamin C and its binding partners expression and localisation are involved in the pathogenesis of HCM in this mouse model.

中文翻译：

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探索机械感知对心肌病的贡献

资金致谢 资金来源类型：基金会。主要资金来源：医学研究委员会 (MR/V009540/1)、威康信托 (201543/B/16/Z) 英国心脏基金会 (FS/12/40/29712)。肥厚型心肌病 (HCM) 是一种与舒张功能障碍和心源性猝死相关的遗传性心脏病。HCM 的疾病基因传统上编码与力产生有关的蛋白质。最近，研究表明，编码与生物力学压力信号有关的蛋白质的基因变异也可能导致 HCM。一种这样的蛋白质是细丝蛋白 C，在心脏中具有机械感应功能。在蛋白质中，免疫球蛋白样结构域 20 (Ig20) 可能在介导与肌肉特异性配体的结合中起关键作用。虽然细丝蛋白 C 的机械传感功能已在骨骼肌中得到很好的研究，但潜在的心脏病机制尚不完全清楚。目的 这项工作试图深入了解细丝蛋白 C 在心脏机械传感中的作用，并在 Ig20 中存在 FLNC 变体的情况下剖析导致 HCM 的疾病途径。方法 使用质谱，我们旨在使用来自 14 周龄纯合小鼠的心室组织样本，对携带细丝蛋白 C 变体的小鼠的蛋白质组进行详细分析。样品经过分子生物学技术和亚细胞分离（每个基因型 n = 6），并通过无标记质谱法进行研究。结果 利用全基因组测序，在受 HCM 影响的三代家族中鉴定了 Ig20 中的杂合 FLNC 错义变体。携带这种变体的小鼠在纯合环境中概括了 HCM 的分子特征。发现三种蛋白质（FLNC、MYH7、MYOT）在富含肌丝的部分中上调。发现关键蛋白质的上调重新定位到负载位点。结论 我们的数据表明，细丝蛋白 C 及其结合伙伴表达和定位的变化参与了该小鼠模型中 HCM 的发病机制。