Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy

@article{Hinson2015TitinMI,
  title={Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy},
  author={J. T. Hinson and Anant Chopra and Navid A Nafissi and William J. Polacheck and Craig C. Benson and S. Swist and J. Gorham and Luhan Yang and S. Schafer and C. Sheng and A. Haghighi and Jason G Homsy and N. Hubner and G. Church and S. Cook and W. Linke and Christopher S. Chen and J. Seidman and C. Seidman},
  journal={Science},
  year={2015},
  volume={349},
  pages={982 - 986}
}
A giant disruption of the heart Certain forms of heart failure originate from genetic mutations. Understanding how the culprit mutant proteins alter normal heart function could lead to more effective treatments. One candidate is the giant protein tintin, which is mutated in a subset of patients with dilated cardiomyopathy. Through a combination of patient-derived stem cells, tissue engineering, and gene editing, Hinson et al. found that disease-associated titin mutations disrupt the function of… Expand
Functional abnormalities in induced Pluripotent Stem Cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy
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The hypothesis that induced Pluripotent Stem Cell (iPSC)-derived cardiomyocytes generated from patients, recapitulate the disease phenotype of titin-mutated patients is investigated, and findings show that the mutated carduomyocytes from DCM patients recapitulates abnormalities of the inherited cardiomeopathies, expressed as blunted inotropic response. Expand
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The role of TTN mutations in development of DCM, how differential expression of Titin isoforms relate to DCM pathophysiology, and how post-translational modifications of titin can affect cardiomyocyte function are reviewed. Expand
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Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies
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  • Medicine
  • International journal of molecular sciences
  • 2019
TLDR
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Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy
TLDR
It is shown that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145), and the identification of TTN mutations in individuals with C MD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover. Expand
Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease
TLDR
It is shown that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations ofTTNtv-positive DCM, and define the penetrance and outcomes of TTNTV in the general population. Expand
Truncations of titin causing dilated cardiomyopathy.
TLDR
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 heart disease. Expand
Dilated cardiomyopathy: the complexity of a diverse genetic architecture
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Reassessment of assumptions about the complexity of the genomic and phenomic architecture of DCM is warranted, which will require comprehensive genomic studies in much larger cohorts of rigorously phenotyped probands and family members than previously examined. Expand
Mutations in the cardiac myosin binding protein–C gene on chromosome 11 cause familial hypertrophic cardiomyopathy
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Cardiac MyBP-C mutations are defined as the cause of FHC on chromosome 11 p and reaffirm that FHC is a disease of the sarcomere. Expand
Titin Isoform Switch in Ischemic Human Heart Disease
TLDR
A titin isoform switch was observed in chronically ischemic human hearts showing extensive remodeling, which necessitated cardiac transplantation, and could impair the ability of the heart to use the Frank-Starling mechanism. Expand
Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction.
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TLDR
Tin and titin-based protein complexes are now recognized as integral parts of the mechanosensitive protein network and as critical components in cardiomyocyte stress/stretch signalling. Expand
Loaded Shortening, Power Output, and Rate of Force Redevelopment Are Increased With Knockout of Cardiac Myosin Binding Protein-C
TLDR
Force, loaded shortening velocities, and rates of force redevelopment were measured during both maximal and half-maximal Ca2+ activations to suggest that cMy BP-C is an important regulator of myocardial work capacity whereby MyBP-C acts to limit power output. Expand
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5'RNA-Seq has the potential to identify genome-wide changes in 5' start-site usage that are associated with pathogenic phenotypes, and indicates that Fhl1 transcriptional changes provide salutary effects on stressed myocytes in this disease. Expand
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The use of TALENs is reported here to rapidly and efficiently generate mutant alleles of 15 genes in cultured somatic cells or human pluripotent stem cells, the latter for which both the targeted lines and isogenic control lines are differentiated into various metabolic cell types. Expand
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