Familial cardiomyopathy is an inherited disease that affects the structure and function of heart muscle and has an extreme range of phenotypes. Among the millions of affected individuals, patients with hypertrophic (HCM), dilated (DCM), or left ventricular non-compaction (LVNC) cardiomyopathy can experience morphologic changes of the heart which lead to sudden death in the most detrimental cases. TNNC1, the gene that codes for cardiac troponin C (cTnC), is a sarcomere gene associated with cardiomyopathies in which probands exhibit young age of presentation and high death, transplant or ventricular fibrillation events relative to TNNT2 and TNNI3 probands. Using GnomAD, ClinVar, UniProt and PhosphoSitePlus databases and published literature, an extensive list to date of identified genetic variants in TNNC1 and post-translational modifications (PTMs) in cTnC was compiled. Additionally, a recent cryo–EM structure of the cardiac thin filament regulatory unit was used to localize each functionally studied amino acid variant and each PTM (acetylation, glycation, s-nitrosylation, phosphorylation) in the structure of cTnC. TNNC1 has a large number of variants (> 100) relative to other genes of the same transcript size. Surprisingly, the mapped variant amino acids and PTMs are distributed throughout the cTnC structure. While many cardiomyopathy-associated variants are localized in α-helical regions of cTnC, this was not statistically significant χ² (p = 0.72). Exploring the variants in TNNC1 and PTMs of cTnC in the contexts of cardiomyopathy association, physiological modulation and potential non-canonical roles provides insights into the normal function of cTnC along with the many facets of TNNC1 as a cardiomyopathic gene.

家族性心肌病是一种遗传性疾病，会影响心肌的结构和功能，并具有极端范围的表型。在数百万受影响的个体中，肥厚型 (HCM)、扩张型 (DCM) 或左心室致密化不全 (LVNC) 心肌病患者可能会经历心脏的形态学变化，在最有害的情况下会导致猝死。TNNC1是编码心肌肌钙蛋白 C (cTnC) 的基因，是与心肌病相关的肌节基因，其中先证者表现出与TNNT2和TNNI3相关的年轻发病年龄和较高的死亡、移植或心室颤动事件先证者。使用 GnomAD、ClinVar、UniProt 和 PhosphoSitePlus 数据库和已发表的文献，编制了迄今为止已识别的TNNC1中的遗传变异和 cTnC中的翻译后修饰 (PTM) 的广泛列表。此外，最近使用心脏细丝调节单元的低温-EM 结构来定位 cTnC 结构中每个功能研究的氨基酸变体和每个 PTM（乙酰化、糖基化、s-亚硝基化、磷酸化）。TNNC1相对于具有相同转录本大小的其他基因，具有大量变体（> 100）。令人惊讶的是，映射的变体氨基酸和 PTM 分布在整个 cTnC 结构中。虽然许多心肌病相关变异位于 cTnC 的 α 螺旋区域，但这在统计学上没有显着性 χ2 ⁽ p = 0.72)。在心肌病关联、生理调节和潜在的非典型作用的背景下探索 cTnC 的TNNC1和 PTM的变体，可以深入了解 cTnC 的正常功能以及TNNC1作为心肌病基因的许多方面。