Titin mutations and muscle disease

  • Dalma Kellermayer
  • John E. Smith3rd
  • Henk GranzierEmail author
Invited Review


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.


Titin Dilated cardiomyopathy Mutations TTNtv Exon skipping 



This study was funded by National Institutes of Health grants R35HL144998, R01AR073179 and Interdisciplinary Training in Cardiovascular Research T32 HL007249.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any primary studies with human participants or animals performed by any of the authors.

Supplementary material

424_2019_2272_MOESM1_ESM.pdf (1.7 mb)
Supplemental Table S1 Domain composition of the metatranscript of titin and Novex-3 titin. Indicated are conventional names for domains based on Bang et al. [11]. Alternative domain names based on TITINdb (, see Laddach et al. [71], and UniProt ( [107]. Accession numbers for the Metatranscript and Novex-3 proteins are NP_001254479 and NP_596870. (PDF 1737 kb)


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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cellular and Molecular MedicineUniversity of ArizonaTucsonUSA
  2. 2.Sarver Molecular Cardiovascular Research ProgramUniversity of ArizonaTucsonUSA

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