Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease

Gramlich, Michael; Michely, Beate; Krohne, Christian; Heuser, Arnd; Erdmann, Bettina; Klaassen, S.; Hudson, Bryan D.; Magarin, Manuela; Kirchner, Florian; Todiras, Mihail; Granzier, Henk; Labeit, Siegfried; Thierfelder, Ludwig; Gerull, Brenda

doi:10.1016/j.yjmcc.2009.04.014

Cited by 94 publications

(109 citation statements)

References 30 publications

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“…On the other hand, when the heterozygous mice were chronically exposed to angiotensin II or isoproterenol, the mice developed marked left ventricular dilatation. 47 Thus, a functional defect in titin may become only apparent under stress. Interestingly, lamin A binds the C-terminus of nuclear titin in a way that might contribute to mechanochemical transduction, 48,49 and thus one can speculate that a combination of LMNA and TTN mutations might have a synergistically deleterious effect on this function.…”

Section: Discussionmentioning

confidence: 99%

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

et al. 2013

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Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/ TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM. With the exception of TTN, truncating mutations of which have been found in up to 27% of individuals with DCM, 1 a single DCM-causing gene accounts for no more than 6-8% of all cases. The known DCM disease genes include those encoding for proteins of the sarcomere, the Z-disk, the cytoskeleton, the mitochondria, RNA binding proteins, the sarcoplasmic reticulum, and the nuclear envelope. 2-4 Familial DCM exhibits a remarkable degree of clinical variability with respect to severity, penetrance, and age of onset. 5 Like familial hypertrophic cardiomyopathy (HCM), familial DCM is often characterized by incomplete penetrance, a high degree of variable expressivity even among

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Section: Discussionmentioning

confidence: 99%

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

et al. 2013

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“…Circumventing the problems associated with the analysis of individual titin domains outside their native environment such as dominant-negative effects and mislocalization, researchers have used tissue-and speciesspecific titin isoform expression and subsequently knockout technology to gain insight into titin's roles in sarcomere assembly and stability and mechanotransduction, as well as in cardiac and skeletal muscle physiology (Weinert et al, 2006;Radke et al, 2007;Gramlich et al, 2009;Granzier et al, 2009). Based on these studies it has been proposed that titin serves as an elastic scaffold to provide both a backbone for proper assembly and localization of sarcomeric proteins and a mechanical basis for the passive functions of striated muscle (Tskhovrebova and Trinick, 2003).…”

Section: Discussionmentioning

confidence: 99%

Titin visualization in real time reveals an unexpected level of mobility within and between sarcomeres

Lopes¹,

Pietas²,

Radkë³

et al. 2011

J Gen Physiol

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“…In a DCM patient mimicking knockin mouse model of truncated A-band titin, an extremely low amount of truncated protein was detected in the hearts of animals heterozygous for the mutation. 102 Whether the truncated titin variant is built into the sarcomere is another (difficult to resolve) issue. In summary, TTN has emerged as an important disease gene in human skeletal and cardiac myopathies.…”

Section: Titin As a Major Human Disease Genementioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

286

232

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With every heartbeat, our cardiomyocytes are exposed to variable degrees of stress and strain of both internal and external origin. The unique mechanical properties of these myocytes are determined by the sarcomeric cytoskeleton. The actin (thin) and myosin (thick) filaments of the sarcomere are mainly relevant for active force generation, whereas the titin filaments determine sarcomeric viscoelasticity. The giant protein titin, which is the focus of this review, has various roles beyond viscoelastic force generation 1-3 : (1) it keeps the thick filaments centered in the sarcomere, allowing optimum active force development; (2) it is important for the assembly of the sarcomeres; (3) it participates in mechano-chemical signaling events via some of its binding partners; and (4) it may be crucial for the length-dependent activation of the contractile apparatus, which underlies the Frank-Starling law. During the past decade, we have learned that titin elasticity is highly variable in the developing and the adult healthy heart and that it can be pathologically altered in heart disease. These alterations greatly affect the extensibility and the diastolic passive stiffness of myocardium and presumably also the mechanosensitivity. Moreover, TTN, which encodes the titin protein, has been recognized as a major human disease gene. In this context, the properties and functions of cardiac titin have become of interest in the continuing search for the molecular origins of human heart disease and the identification of novel potential targets for therapeutic intervention. In our review, we begin with a short clinical perspective establishing the link between diastolic stiffness and titin and briefly compare the importance of titin versus collagen for myocardial passive stiffness. We then cover some details of titin protein structure and elasticity, before summarizing how titin-binding partners affect titin properties and broaden the range of titin functions, with a special focus on the standing of titin in pathways of protein quality control. We continue with a current overview of titin mutations in human skeletal muscle and heart disease. The remainder of the review deals with the contribution of titin to diastolic stiffness and how it is modulated in normal and failing hearts by mechanisms such as titin-isoform switching, titin phosphorylation (including heart failure [HF]-related alterations of it), and oxidative modifications. Clinical Context: Diastolic Function and Diastolic AbnormalitiesDiastolic function has moved into the focus of HF research, because an increasing number of patients with HF (≥50%) present with diastolic rather than systolic dysfunction. 4 Common abnormalities of diastolic function include impaired left ventricular (LV) relaxation, decreased LV distensibility, increased LV end-diastolic stiffness, and pericardial and right ventricular constraint. These abnormalities have been suggested to be contributing factors in diastolic HF or HF with a preserved ejection fraction (HFpEF).5 HFpEF is accompanied by ...

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Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease

Cited by 94 publications

References 30 publications

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Titin visualization in real time reveals an unexpected level of mobility within and between sarcomeres

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