Regulation of TTN as a mechanism of and treatment for heart failure
Dominic E. Fullenkamp
Dominic E. Fullenkamp
Published February 17, 2025
Citation Information: J Clin Invest. 2025;135(4):e189335. https://doi.org/10.1172/JCI189335.
View: Text | PDF
Commentary

Regulation of TTN as a mechanism of and treatment for heart failure

Abstract

Truncation variants in the gene TTN encoding titin are the most common cause of familial dilated cardiomyopathy (DCM), with both haploinsufficiency and “poison peptide” implicated as contributory mechanisms of disease. In this issue of the JCI, Kim et al. identify a highly conserved enhancer element approximately 500 bp downstream of the transcriptional start site of TTN in intron 1, which they demonstrated to be critical in regulating TTN expression. This work helps to further clarify the relative role of haploinsufficiency in TTN-related DCM and provides a potential target for therapies aimed at treating TTN-related DCM.

Authors

Dominic E. Fullenkamp

×

Figure 1

TTN encodes the giant myofilament protein TTN that spans the full half-sarcomere.

Options: View larger image (or click on image) Download as PowerPoint
TTN encodes the giant myofilament protein TTN that spans the full half-...
TTN spans the Z-disc to the M-line in the half-sarcomere and has a structural role. The intron 1 enhancer identified by Kim et al. is approximately 500 bp downstream of the TTN transcriptional start site (18), with the translational start site found in exon 2. The I-band is variably spliced to give the dominant cardiac isoforms N2B and N2BA. An alternative promoter near the A/I junction gives rise to the Cronos isoform (3).