Truncations of titin causing dilated cardiomyopathy
Open accessAbstract
BACKGROUND: Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size. METHODS: We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics. RESULTS: We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)). CONCLUSIONS: TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.).
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SORBS1 and MAP4K4 had multiple noncanonical isoforms that were detectable across multiple tissues, whereas titin had the most isoforms identified.
“A number of proteins including SORBS1 and MAP4K4 had multiple noncanonical isoforms that were detectable across multiple tissues, whereas the protein with the most isoforms identified was titin (Figure 3A), which is also the largest protein in the human genome with the most exons and whose splicing has been widely implicated in congenital heart diseases (Guo et al., 2012; Herman et al., 2012).”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Herman et al., 2012
Mutations in TTN are associated with familial dilated cardiomyopathy in humans.
“mutations in TTN are associated with familial dilated cardiomyopathy (Herman et al., 2012).”
From Population genomics reveal recent speciation and rapid evolutionary adaptation in polar bears (2014) · cites this paper as Herman et al., 2012
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- Authors
- Herman, D. S., Lam, L., Taylor, M. R. G., Wang, L., Teekakirikul, P., Christodoulou, D., Conner, L., DePalma, S. R., McDonough, B., Sparks, E., Teodorescu, D. L., Cirino, A. L., Banner, N. R., Pennell, D. J., Graw, S., Merlo, M., Di Lenarda, A., Sinagra, G., Bos, J. M., Ackerman, M. J., Mitchell, R. N., Murry, C. E., Lakdawala, N. K., Ho, C. Y., Barton, P. J. R., Cook, S. A., Mestroni, L., Seidman, J. G., & Seidman, C. E.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- University of Colorado Denver (US)
- Brigham and Women's Hospital (US)
- Royal Brompton & Harefield NHS Foundation Trust (GB)
- University of Trieste (IT)
- Mayo Clinic (US)
- University of Washington (US)
- Imperial College London (GB)
- ORCID
- Herman, Daniel S.
- Lam, Lien
- Taylor, Matthew R.G.
- Wang, Libin
- Teekakirikul, Polakit
- DePalma, Steven R.
- McDonough, Barbara
- Teodorescu, Debbie Lin
- Cirino, Allison L.
- Banner, Nicholas R.
- Pennell, Dudley J.
- Graw, Sharon
- Merlo, Marco
- Sinagra, Gianfranco
- Bos, J. Martijn
- Ackerman, Michael J.
- Mitchell, Richard N.
- Murry, Charles E.
- Lakdawala, Neal K.
- Ho, Carolyn Y.
- Barton, Paul J.R.
- Cook, Stuart A.
- Mestroni, Luisa
- Seidman, J.G.
- Seidman, Christine E.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-02-16
- Volume
- 366
- Issue
- 7
- Pages
- 619-628
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3660031
- OpenAlex
- W2167989424
- Cited by
- 1,485
- References
- 43
- Citations by year
- 2026: 83 · 2025: 105 · 2024: 130 · 2023: 113 · 2022: 99 · 2021: 144 · 2020: 109 · 2019: 107 · 2018: 101 · 2017: 114 · 2016: 88 · 2015: 79 · 2014: 77 · 2013: 87 · 2012: 46
- FWCI
- 59.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- British Heart Foundation (SP/10/10/28431)
- National Institutes of Health (n01hv48194-8-0-1, UL1TR001082, 1u01hl098166-01)
- National Heart, Lung, and Blood Institute (U01-HL098166, U01HL066582, R01HL084553, N01 HV048194, P01HL059139, P50HL052320, N01-HV-48194, R01HL080494)
- National Institute of General Medical Sciences (T32GM007753)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- titin, TTN gene, dilated cardiomyopathy, hypertrophic cardiomyopathy, truncating mutations, sarcomere proteins, genetic testing, familial cardiomyopathy, mutation penetrance, nonsense mutation, frameshift mutation, splicing mutation
- MeSH terms
- Adult, Cardiomyopathy, Dilated, Female, Humans, Male, Middle Aged, Muscle Proteins, Mutation, Myocardium, Protein Kinases, Sequence Deletion, Sequence Analysis, DNA, Genotyping Techniques, Connectin
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