TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance.
TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance.
复制标题
DOI：
10.1172/jci175206
复制
发表时间：
2024-01-16
影响因子：
15.9
通讯作者：
Campbell, Stuart G.
中科院分区：
文献类型：
--
作者：
Hinson, J. Travis;Campbell, Stuart G.
肌联蛋白(TTN)是人类表达的最大、最复杂的蛋白质之一，截断变异体是扩张型心肌病(DCM)或其他心脏收缩功能受损的个体中最常见的基因损伤。本期JCI的两篇报告阐明了涉及截断TTN肌节整合的潜在机制以及肌节结构完整性破坏的可能性。Kellermayer、Tordai及其同事证实，在人类DCM样本中存在截短的TTN蛋白。McAfee和作者开发了一种患者特异性TTN抗体，以研究截短的TTN亚细胞定位，并探索其功能后果。出现了一种“毒肽”机制，它启发了其他治疗方法，同时为研究开辟了新的途径，例如全长TTN蛋白单倍体不足的作用，解释肌节功能障碍的机制，以及对可变外显率的解释。
Titin (TTN) is one of the largest and most complex proteins expressed in humans, and truncation variants are the most prevalent genetic lesion identified in individuals with dilated cardiomyopathy (DCM) or other disorders of impaired cardiac contractility. Two reports in this issue of the JCI shed light on a potential mechanism involving truncated TTN sarcomere integration and the potential for disruption of sarcomere structural integrity. Kellermayer, Tordai, and colleagues confirmed the presence of truncated TTN protein in human DCM samples. McAfee and authors developed a patient-specific TTN antibody to study truncated TTN subcellular localization and to explore its functional consequences. A “poison peptide” mechanism emerges that inspires alternative therapeutic approaches while opening new lines for inquiry, such as the role of haploinsufficiency of full-length TTN protein, mechanisms explaining sarcomere dysfunction, and explanations for variable penetrance.