Titin (TTN) is the largest protein in humans, and TTN truncating variants (TTNtv; SNPs that lead to premature stop codons, indels that cause frameshifts in the coding sequence and variants that disrupt canonical splice sites) have recently been shown to be the leading genetic cause of Dilated Cardiomyopathy (DCM), present in up to 25% of cases (Herman et al, NEJM 2012). TTNtv are also found in approximately 1% of healthy individuals.
We are studying the relationship between TTNtv and cardiomyopathy - to determine why some individuals with TTNtv are healthy while others are not; to determine whether DCM associated with TTNtv is clinically distinct from other forms of DCM; and to dissect the molecular mechanisms by which TTNtv exert their effects.
To aid in the description and characterisation of TTN variants, we have worked with the European Bioinformatics Institute and TTN locus-specific database to develop a Locus Reference Genomic for TTN, and have used RNA sequencing to determine exon-level expression in human heart tissue. This webpage provides access to these combined annotations for all TTN exons (364) and principal human isoforms, to aid the interpretation of TTNtv, as well as detailing the TTNtv identified in major published studies of cardiomyopathy. We have developed this resource in conjunction with the following study:
A. M. Roberts, J. S. Ware, D. S. Herman et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci. Transl. Med. 7, 270ra6 (2015) - PDF download.
Distribution of TTN truncating variants (frameshift, nonsense, essential splice site) in DCM patients and controls (from cohorts described in Herman et al and Roberts et al). TTN protein bands are coloured - Z-disc (red), I-band (blue), A-band (green), M-band (purple). Exon usage describes the relative incorporation into transcripts expressed in cardiac tissue as descibed in Roberts et al.
In rats, TTNtv display position-independent nonsense-mediated degradation of mutant alleles, a signature of perturbed cardiac metabolism
and normal heart physiology that became impaired during cardiac stress. In healthy humans, TTNtv are associated with eccentric cardiac remodeling.
Titin-truncating variants affect heart function in disease cohorts and the general population.
Schafer S, de Marvao A et al. Nat Genet. 2016 doi: 10.1038/ng.3719.
Recovery following medical therapy and LVAD support is possible in in DCM patients with titin truncations and may be comparable to genotype-negative patients.
Recovery of Cardiac Function in Cardiomyopathy Caused by Titin Truncation.
Felkin LE, Walsh R, Ware JS, Yacoub MH, Birks EJ, Barton PJ, Cook SA. JAMA Cardiol. 2016 May 1;1(2):234-5.
The prevalence of TTN truncations in a cohort of 172 women with peripartum cardiomyopathy is similar to that observed in DCM, with TTNtv associated with
lower EF at one year follow-up.
Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.
Ware JS, Li J, Mazaika E, Yasso CM et al. N Engl J Med. 2016 Jan 21;374(3):233-41.
Mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and beta-adrenergic stress,
and attenuated growth factor and cell signaling activation.
Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy.
Hinson JT, Chopra A, Nafissi N et al. Science. 2015 Aug 28;349(6251):982-6.
Sequencing of TTN in 5267 DCM and healthy individuals, along with RNA and protein analyses of human heart tissues,
enables discrimination of pathogenic from benign TTNtv and yields evidence for a length-dependent mechanism of disease.
Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.
Roberts AM, Ware JS, Herman DS et al. Sci Transl Med. 2015 Jan 14;7(270):270ra6.
Truncations in TTN are the most common cause of DCM, occurring in 25% of familial and 18% of sporadic cases,
with these variants over-represented in the titin A-band.
Truncations of titin causing dilated cardiomyopathy.
Herman DS, Lam L, Taylor MR et al. N Engl J Med. 2012 Feb 16;366(7):619-28.