Jadidi Motahareh, Babaali Vida, InanlooRahatloo Kolsoum, Salehi Najmeh, Mollazadeh Reza
Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
Department of Applied Biological Sciences, School of Biology, College of Science, University of Tehran, Tehran, Iran.
Eur J Med Res. 2025 May 28;30(1):424. doi: 10.1186/s40001-025-02692-3.
Dilated cardiomyopathy (DCM) is a prevalent etiology of heart failure, distinguished by the gradual and frequently irreversible myocardial muscle impairment. Roughly 50% of DCM occurrences stem from hereditary rare variants. In this study, our aim was to identify the genetic cause of DCM in a pedigree with several affected individuals across four generations.
Whole exome sequencing was performed on the proband, with variants filtered and analyzed using in silico tools. Co-segregation analysis was conducted using Sanger sequencing. Protein structure modeling and protein-protein interaction evaluations were performed using AlphaFold3 and HADDOCK2.4, respectively.
We identified a missense rare variant in the TNNT3 gene, leading to the p.Glu125Gly alteration in the Troponin T3 (TNNT3). This rare variant is strongly implicated as the causative factor for DCM in the pedigree. Several key factors underscore its significance: the rare variant co-segregates with the disease in the pedigree, is absent in 850 control samples, alters a conserved amino acid, is predicted to detrimentally affect protein function, and results in structural changes.
Our findings suggest that TNNT3 rare variants can induce DCM by weakening the binding energy between TNNT3 and Tropomyosin (TPM), leading to functional deficiencies in muscle contraction, as demonstrated by our structural modeling and docking studies. Troponin T is essential for the proper contraction of striated muscles and is related to cardiac development. Bioinformatics investigations have elucidated the involvement of TNNT3-related pathways, notably the Striated Muscle Contraction pathway and Cardiac Conduction. TNNT3 resides within loci previously implicated in cardiomyopathy. Given its crucial role in muscle contractile function, rare variants in TNNT3 hold the potential to be a significant contributing factor in the pathogenesis of DCM. A wealth of literature substantiates the correlation between troponin T and cardiac disorders. Our findings further corroborate this association.
扩张型心肌病（DCM）是心力衰竭的常见病因，其特征是心肌逐渐受损且常为不可逆性。大约50%的DCM病例源于遗传性罕见变异。在本研究中，我们的目的是确定一个四代中有多个患病个体的家系中DCM的遗传病因。
对先证者进行全外显子测序，使用计算机工具对变异进行筛选和分析。使用Sanger测序进行共分离分析。分别使用AlphaFold3和HADDOCK2.4进行蛋白质结构建模和蛋白质-蛋白质相互作用评估。
我们在TNNT3基因中鉴定出一个错义罕见变异，导致肌钙蛋白T3（TNNT3）中的p.Glu125Gly改变。这个罕见变异被强烈认为是该家系中DCM的致病因素。几个关键因素突出了其重要性：该罕见变异在家系中与疾病共分离，在850个对照样本中不存在，改变了一个保守氨基酸，预计会对蛋白质功能产生不利影响，并导致结构变化。
我们的研究结果表明，TNNT3罕见变异可通过削弱TNNT3与原肌球蛋白（TPM）之间的结合能来诱发DCM，导致肌肉收缩功能缺陷，正如我们的结构建模和对接研究所证明的那样。肌钙蛋白T对于横纹肌的正常收缩至关重要，并且与心脏发育有关。生物信息学研究已经阐明了TNNT3相关途径的参与，特别是横纹肌收缩途径和心脏传导。TNNT3位于先前与心肌病相关的基因座内。鉴于其在肌肉收缩功能中的关键作用，TNNT3中的罕见变异有可能成为DCM发病机制中的一个重要促成因素。大量文献证实了肌钙蛋白T与心脏疾病之间的相关性。我们的研究结果进一步证实了这种关联。
