The prevalent I686T human variant and loss-of-function mutations in the cardiomyocyte-specific kinase gene TNNI3K cause adverse contractility and concentric remodeling in mice

Hum Mol Genet. 2021 Jan 6;29(21):3504-3515. doi: 10.1093/hmg/ddaa234.


TNNI3K expression worsens disease progression in several mouse heart pathology models. TNNI3K expression also reduces the number of diploid cardiomyocytes, which may be detrimental to adult heart regeneration. However, the gene is evolutionarily conserved, suggesting a beneficial function that has remained obscure. Here, we show that C57BL/6J-inbred Tnni3k mutant mice develop concentric remodeling, characterized by ventricular wall thickening and substantial reduction of cardiomyocyte aspect ratio. This pathology occurs in mice carrying a Tnni3k null allele, a K489R point mutation rendering the protein kinase-dead, or an allele corresponding to human I686T, the most common human non-synonymous TNNI3K variant, which is hypomorphic for kinase activity. Mutant mice develop these conditions in the absence of fibrosis or hypertension, implying a primary cardiomyocyte etiology. In culture, mutant cardiomyocytes were impaired in contractility and calcium dynamics and in protein kinase A signaling in response to isoproterenol, indicating diminished contractile reserve. These results demonstrate a beneficial function of TNNI3K in the adult heart that might explain its evolutionary conservation and imply that human TNNI3K variants, in particular the widespread I686T allele, may convey elevated risk for altered heart geometry and hypertrophy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Heart Diseases / etiology
  • Heart Diseases / metabolism
  • Heart Diseases / pathology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Muscle Contraction*
  • Mutation*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology*
  • Protein Serine-Threonine Kinases / genetics*
  • Vascular Remodeling*


  • Tnni3k protein, mouse
  • Protein Serine-Threonine Kinases
  • TNNI3K protein, human