Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy

Arimura, Takuro; Bos, J. Martijn; Sato, Akinori; Kubo, Toru; Okamoto, Hiroshi; Nishi, Hirofumi; Harada, Haruhito; Koga, Yoshinori; Moulik, Mousumi; Doi, Yoshinori; Towbin, Jeffrey A.; Ackerman, Michael J.; Kimura, Akinori

doi:10.1016/j.jacc.2008.12.082

Cited by 140 publications

(114 citation statements)

References 25 publications

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“…HCM-associated mutations in TTN seem to be rarer than DCM-associated mutations 90 and they seem to affect predominantly the Z-disk/I-band region (Figure 4). 82,90,97 For restrictive cardiomyopathy, a small family with a mutation in the ninth FNIII domain at the I-band/A-band junction has been reported. 98 The 8 arrhythmogenic right ventricular cardiomyopathyassociated mutations identified to date are distributed all over the TTN sequence.…”

Section: Titin As a Major Human Disease Genementioning

confidence: 99%

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Linke

Hamdani

2014

Circulation Research

280

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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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Section: Titin As a Major Human Disease Genementioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

280

223

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“…Neonatal rat cardiomyocytes (NRCs) from one-day-old Sprague-Dawley rats were prepared as described previously [Arimura et al, 2009]. NRCs (1 × 10 4 cells) were plated onto the Collagen Type I Cellware 8-Well Culture Slide (BD Biosciences, MA) in low-glucose DMEM supplemented with 0.01 mg/ml insulin (Sigma-Aldrich, MO), 10% fetal bovine serum (FBS), and 1% penicillin/streptomycin at 37…”

Section: Indirect Immunofluorescence Microscopymentioning

confidence: 99%

Dilated cardiomyopathy-associatedBAG3mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes

et al. 2011

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Dilated cardiomyopathy (DCM) is characterized by dilation of left ventricular cavity with systolic dysfunction. Clinical symptom of DCM is heart failure, often associated with cardiac sudden death. About 20-35% of DCM patients have apparent family histories and it has been revealed that mutations in genes for sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in about 17% of Japanese patients with familial DCM. Bcl-2-associated athanogene 3 (BAG3) is a co-chaperone protein with antiapoptotic function, which localizes at Z-disc in the striated muscles. Recently, BAG3 gene mutations in DCM patients were reported, but the functional abnormalities caused by the mutations are not fully unraveled. In this study, we analyzed 72 Japanese familial DCM patients for mutations in BAG3 and found two mutations, p.Arg218Trp and p.Leu462Pro, in two cases of adult-onset DCM without skeletal myopathy, which were absent from 400 control subjects. Functional studies at the cellular level revealed that the DCM-associated BAG3 mutations impaired the Z-disc assembly and increased the sensitivities to stress-induced apoptosis. These observations suggested that BAG3 mutations present in 2.8% of Japanese familial DCM patients caused DCM possibly by interfering with Z-disc assembly and inducing apoptotic cell death under the metabolic stress.

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“…There are several other disease genes for HCM, including mutations in caveolin-3 gene (CAV3), 40 meta-vinculin gene (VCL), 41 aB-crystallin gene (CRYAB), 42 junctophilin-2 gene (JPH-2), 43 obscurin gene (OBSCN) 44 and most recently reported CARP gene (ANKRD1) 45 ( Figure 2). Functional analyses were reported for CRYAB, CAV3, OBSCN and ANKRD1 mutations; aggregation of aB-crystalline in cytoplasm, 42 decreased cell surface expression of caveolin-3, 40 decreased binding to titin, 44 and increased binding to titin and myopalladin, 45 respectively.…”

Section: Other Mutations In Hcmmentioning

confidence: 99%

“…Functional analyses were reported for CRYAB, CAV3, OBSCN and ANKRD1 mutations; aggregation of aB-crystalline in cytoplasm, 42 decreased cell surface expression of caveolin-3, 40 decreased binding to titin, 44 and increased binding to titin and myopalladin, 45 respectively. It is not clear how the aggregated aB-crystalline resulted in cardiac hypertrophy, but impaired stress response may exaggerate hypertrophic response.…”

Section: Other Mutations In Hcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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Cardiomyopathy is caused by functional abnormality of cardiac muscle. The functional abnormality involved in its etiology includes both extrinsic and intrinsic factors, and cardiomyopathy caused by the intrinsic factors is called as idiopathic or primary cardiomyopathy. There are several clinical types of primary cardiomyopathy including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Linkage studies and candidate gene approaches have explored the disease genes for hereditary primary cardiomyopathy. The most notable finding was that mutations in the same disease gene can be found in different clinical types of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical types, such that increased and decreased Ca 2+ sensitivity due to sarcomere mutations are associated with HCM and DCM, respectively. In addition, our recent studies have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of sarcomere; that is, stiff sarcomere and loose sarcomere, respectively, and hence altered stretch response. More recently, mutations in the components of I region were found in hereditary cardiomyopathy and the functional analyses of the mutations suggested that the altered stress response was associated with cardiomyopathy, further complicating the etiology and pathogenesis. However, elucidation of genetic etiology and functional alterations caused by the mutations shed lights on the new therapeutic approaches to hereditary cardiomyopathy, such that treatment of DCM with a Ca 2+ sensitizer prevented the disease in a mouse model.

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Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy

Abstract: CARP abnormalities may be involved in the pathogenesis of HCM.

Cited by 140 publications

References 25 publications

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Dilated cardiomyopathy-associatedBAG3mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

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