Sarcomeric Protein Mutations in Dilated Cardiomyopathy

Chang, Audrey N.; Potter, James D.

doi:10.1007/s10741-005-5252-6

Cited by 130 publications

(108 citation statements)

References 70 publications

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“…66 Therefore, sarcomere mutations can be found in both HCM and DCM, but difference in the functional alterations may determine the different phenotypes. 67 …”

Section: Sarcomere Mutations In Dcmmentioning

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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“…66 Therefore, sarcomere mutations can be found in both HCM and DCM, but difference in the functional alterations may determine the different phenotypes. 67 …”

Section: Sarcomere Mutations In Dcmmentioning

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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“…TNNT2 is a sarcomeric protein important for proper contraction of cardiomyocytes. In humans, mutations in TNNT2 have been found in patients with late-onset dilated cardiomyopathy 55 which, similarly to mutations in dystrophin, may create predisposition to enteroviral infection and consequent tissue damage. Vms3 on chromosome 4 is bound within a much smaller locus, containing 109 genes.…”

Section: Genetic Control Of Viral Myocarditis In Micementioning

confidence: 99%

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

et al. 2007

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The pathogenesis of viral myocarditis is a multifactorial process involving host genetics, viral genetics and the environment in which they interact. We have used a model of infection with coxsackievirus B3 (CVB3) to characterize the contribution of host genetics to viral myocarditis in mice of different genetic backgrounds but with a common H2 haplotype: A/J and B10.A-H2 a .Here we have used Evans blue dye as a quantitative biomarker for susceptibility to CVB3-induced myocarditis in addition to histopathological semiquantitative measures. We have found evidence of linkage between susceptibility to viral myocarditis and three loci. A locus on chromosome 1 centered on D1Mit200 was linked to sarcolemmal disruption in males (P ¼ 0.00005), a second locus on chromosome 4 centered on D4Mit81 was also linked to sarcolemmal disruption in males (P ¼ 0.0022). A third locus on distal chromosome 3 centered on D3Mit19 was linked to myocardial infiltration, with a logarithm of odds (LOD) score of 4.7 (P ¼ 0.0045), as well as sarcolemmal disruption in females (P ¼ 0.0015). These results provide strong evidence for the presence of loci contributing to the susceptibility of mice to viral myocarditis.

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“…Epidemiological studies addressing the prevalence of gene mutations in DCM patients have demonstrated that inherited forms account for at least one-third of all DCM cases. [1][2][3][4] Familial cases frequently show a monogenic origin, and transmission indicates autosomal dominant or X-linked inheritance pattern with incomplete and age-dependent penetrance. 3 To date, positional cloning and candidate gene screening have led to the identification of numerous heterozygous mutations in more than 40 different genes, most of which encode proteins important for the structural integrity and function of cardiomyocytes, such as regulatory proteins of the sarcomere, the nuclear envelope or intracellular homeostasis.…”

Section: Introductionmentioning

confidence: 99%

“…3 To date, positional cloning and candidate gene screening have led to the identification of numerous heterozygous mutations in more than 40 different genes, most of which encode proteins important for the structural integrity and function of cardiomyocytes, such as regulatory proteins of the sarcomere, the nuclear envelope or intracellular homeostasis. 1,2,5 In particular, defects in proteins required for force transduction and force transmission of the sarcomeric apparatus seem to promote the development of DCM.…”

Section: Introductionmentioning

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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Sarcomeric Protein Mutations in Dilated Cardiomyopathy

Cited by 130 publications

References 70 publications

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

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

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

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

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