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Titin mutations and muscle disease.

ABSTRACT: The introduction of next-generation sequencing technology has revealed that mutations in the gene that encodes titin (TTN) are linked to multiple skeletal and cardiac myopathies. The most prominent of these myopathies is dilated cardiomyopathy (DCM). Over 60 genes are linked to the etiology of DCM, but by far, the leading cause of DCM is mutations in TTN with truncating variants in TTN (TTNtvs) associated with familial DCM in ??20% of the cases. Titin is a large (3-4 MDa) and abundant protein that forms the third myofilament type of striated muscle where it spans half the sarcomere, from the Z-disk to the M-line. The underlying mechanisms by which titin mutations induce disease are poorly understood and targeted therapies are not available. Here, we review what is known about TTN mutations in muscle disease, with a major focus on DCM. We highlight that exon skipping might provide a possible therapeutic avenue to address diseases that arise from TTNtvs.

SUBMITTER: Kellermayer D

PROVIDER: S-EPMC6481931 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Titin mutations and muscle disease.

Kellermayer Dalma D Smith John E JE Granzier Henk H

Pflugers Archiv : European journal of physiology 20190327 5

The introduction of next-generation sequencing technology has revealed that mutations in the gene that encodes titin (TTN) are linked to multiple skeletal and cardiac myopathies. The most prominent of these myopathies is dilated cardiomyopathy (DCM). Over 60 genes are linked to the etiology of DCM, but by far, the leading cause of DCM is mutations in TTN with truncating variants in TTN (TTNtvs) associated with familial DCM in ∼ 20% of the cases. Titin is a large (3-4 MDa) and abundant protein th ...[more]

PMID: 30919088

Similar Datasets

Titin-based mechanosensing modulates muscle hypertrophy.

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Nature of PEVK-titin elasticity in skeletal muscle.

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Amyloid Aggregates of Smooth-Muscle Titin Impair Cell Adhesion.

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RNA-seq of zebrafish embryos with mutations in a muscle-specific kinase and the giant titin protein

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2024-02-09 | E-MTAB-12934 | biostudies-arrayexpress

HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy.

Project description:Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.

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