Titin Mutations as the Molecular Basis for Dilated Cardiomyopathy

Itoh-Satoh, Manatsu; Hayashi, Takeharu; Nishi, Hirofumi; Koga, Yoshinori; Arimura, Takuro; Koyanagi, Takeshi; Takahashi, Megumi; Hohda, Shigeru; Ueda, Kazuo; Nouchi, Toshihiko; Hiroe, Michiaki; Marumo, Fumiaki; Imaizumi, Tsutomu; Yasunami, Michio; Kimura, Akinori

doi:10.1006/bbrc.2002.6448

Cited by 230 publications

(179 citation statements)

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“…As a number of missense mutations in genes encoding for titin and titin-associated proteins have recently been reported to be responsible for DCM, 3,[12][13][14][15][19][20][21][22][23][24][25] we searched in a well-characterized sample of DCM patients for unknown SNPs and/or mutations in the human MYPN and ANKRD1 genes. In order to extend our knowledge on disease-causing mutations in these two proteins expressed in heart tissue, we screened the coding sequences and corresponding intron flanks of the two genes and found two novel non-synonymous mutations in the MYPN gene and only one rare synonymous SNP in the coding region of the ANKRD1 gene.…”

Section: Discussionmentioning

confidence: 99%

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

et al. 2012

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on behalf of the German Competence Network Heart Failure Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARPencoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the a-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and a-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating that disturbed myofibrillogenesis and altered sarcomere assembly are the cause of the disease. In the ANKRD1 gene, we identified synonymous base exchanges (c.108T4C and c.-79C4T, respectively), but no non-synonymous mutations. In summary, we have identified novel missense mutations in the third immunoglobulin-like domain of myopalladin, which have either no or profound effects on the molecular composition of the sarcomere. According to our epidemiological data, the prevalence of ANKRD1 mutations seems to be lower than that of its binding partner myopalladin, indicating the clinical significance of myopalladin for the functional integrity of the sarcomeric apparatus and the protection against DCM.

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Section: Discussionmentioning

confidence: 99%

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

et al. 2012

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“…TTN mutations have been found in patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and various types of skeletal myopathies. Already the first reports on human titin mutations suggested that they can occur in all parts of the molecule [82][83][84][85][86][87] and the 125 currently known mutations are indeed scattered all over the TTN gene, without a clear hotspot (Figure 4). A notable exception may be a rare muscle disease, hereditary myopathy with early respiratory failure, which seems to be caused by mutations in exon 343 encoding the 119th FNIII domain of A-band titin (see Online Table I, for references).…”

Section: Titin As a Major Human Disease Genementioning

confidence: 99%

“…90 The majority of the TTN mutations found in DCM patients are truncating mutations within A-band titin, but I-band mutations and a few Z-disk and M-band (including TK) mutations have also been reported ( Figure 4). 83,84,[90][91][92][93][94][95][96] These mutations include mostly nonsense and frameshift as well as splicing variants. Some patients with a titin mutation present with both cardiac and skeletal muscle disease, 91,96 but often it is unknown whether in patients with a cardiac phenotype the skeletal muscles are affected as well.…”

Section: Titin As a Major Human Disease Genementioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

292

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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“…The two major titin splice forms, N2B and N2BA, vary in their expression in pathological states, including cardiomyopathies (187,232). In addition, titin mutations may cause DCM in a subset of patients (232).…”

Section: Hypertrophic Cardiomyopathymentioning

confidence: 99%