Document Type

Article

Publication Date

1-16-2024

Keywords

JGM, Humans, Connectin, Sarcomeres, Cardiomyopathy, Dilated, Penetrance, Mutation

JAX Source

J Clin Invest. 2024;134(2).

ISSN

1558-8238

PMID

38226618

DOI

https://doi.org/10.1172/jci175206

Grant

Funding supported was obtained from the NIH (R01HL165220, to JTH and SGC).

Abstract

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.

Comments

This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

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