Exon-and contraction-dependent functions of titin in sarcomere assembly

Yu Huan Shih, Alexey V. Dvornikov, Ping Zhu, Xiao Ma, Maengjo Kim, Yonghe Ding, Xiaolei Xu

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Titin-truncating variants (TTNtvs) are the major cause of dilated cardiomyopathy (DCM); however, allelic heterogeneity (TTNtvs in different exons) results in variable phenotypes, and remains a major hurdle for disease diagnosis and therapy. Here, we generated a panel of ttn mutants in zebrafish. Four single deletion mutants in ttn.2 or ttn.1 resulted in four phenotypes and three double ttn.2/ttn.1 mutants exhibited more severe phenotypes in somites. Protein analysis identified ttnxu071 as a near-null mutant and the other six mutants as hypomorphic alleles. Studies of ttnxu071 uncovered a function of titin in guiding the assembly of nascent myofibrils from premyofibrils. By contrast, sarcomeres were assembled in the hypomorphic ttn mutants but either became susceptible to biomechanical stresses such as contraction or degenerated during development. Further genetic studies indicated that the exon usage hypothesis, but not the toxic peptide or the Cronos hypothesis, could account for these exondependent effects. In conclusion, we modeled TTNtv allelic heterogeneity during development and paved the way for future studies to decipher allelic heterogeneity in adult DCM.

Original languageEnglish (US)
Pages (from-to)4713-4722
Number of pages10
JournalDevelopment (Cambridge)
Issue number24
StatePublished - Dec 15 2016


  • Allelic heterogeneity
  • Sarcomere assembly
  • Titin
  • Zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


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