Titin, the so-called “third filament” of the sarcomere, represents a difficult challenge for the determination of damaging genetic variants. A single titin molecule extends across half the length of a sarcomere in striated muscle, fulfilling a variety of vital structural and signaling roles, and has been linked to an equally varied range of myopathies, resulting in a significant burden on individuals and healthcare systems alike. While the consequences of truncating variants of titin are well-documented, the ramifications of the missense variants prevalent in the general population are less so. We here present a compendium of titin missense variants—those that result in a single amino-acid substitution in coding regions—reported to be pathogenic and discuss these in light of the nature of titin and the variant position within the sarcomere and their domain, the structural, pathological, and biophysical characteristics that define them, and the methods used for characterization. Finally, we discuss the current knowledge and integration of the multiple fields that have contributed to our understanding of titin-related pathology and offer suggestions as to how these concurrent methodologies may aid the further development in our understanding of titin and hopefully extend to other, less well-studied giant proteins.

中文翻译：

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与巨人同行：巨型肌节蛋白肌联变异影响评估的挑战

肌联蛋白，即所谓的肌节的“第三丝”，对于确定破坏性遗传变异来说是一个艰巨的挑战。单个肌联蛋白分子延伸横跨横纹肌肌节的一半长度，履行各种重要的结构和信号传导作用，并且与同样不同范围的肌病有关，给个人和医疗保健系统造成重大负担。虽然肌联蛋白截短变体的后果已有充分记录，但普通人群中普遍存在的错义变体的后果却鲜有记载。我们在这里介绍了肌联蛋白错义变异的概要——那些导致编码区单个氨基酸取代的变异——据报道具有致病性，并根据肌联蛋白的性质和肌节及其结构域内的变异位置进行讨论。定义它们的结构、病理和生物物理特征，以及用于表征的方法。最后，我们讨论了有助于我们理解肌联蛋白相关病理学的当前知识和多个领域的整合，并就这些并行方法如何帮助我们进一步发展对肌联蛋白的理解提供建议，并希望扩展到其他较少的领域。经过充分研究的巨型蛋白质。