Actin Mutations in Dilated Cardiomyopathy, a Heritable Form of Heart Failure

Olson, Timothy M.; Michels, Virginia V.; Thibodeau, Stephen N.; Tai, Yin-Shan; Keating, Mark T.

doi:10.1126/science.280.5364.750

Cited by 607 publications

(366 citation statements)

References 20 publications

(3 reference statements)

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“…However, even mutations in a single cytoskeletal protein, cardiac ␣-actin, result in either DCM or hypertrophic cardiomyopathy (Olson et al, 1998). Moreover, not only mutations in the sarcomeric and cytoskeletal proteins but also genetic modifications in signaling molecule expression can cause DCM or hypertrophic cardiomyopathy.…”

Section: Figurementioning

confidence: 99%

Overexpression of Polycomb-Group Gene rae28 in Cardiomyocytes Does Not Complement Abnormal Cardiac Morphogenesis in Mice Lacking rae28 But Causes Dilated Cardiomyopathy

Koga

Kaji

Nishii

et al. 2002

Laboratory Investigation

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SUMMARY:The Polycomb-group genes (PcG) are widely conserved from Drosophila to mammals and are required for maintaining positional information during development. The rae28 gene (rae28) is a member of the mouse PcG. Mice deficient in rae28 (rae28 Ϫ/Ϫ ) demonstrated that rae28 has a role not only in anteroposterior patterning but also in cardiac morphogenesis. In this study we generated transgenic mice with ubiquitous or cardiomyocyte-specific exogenous rae28 expression. Genetic complementation experiments with these transgenic mice showed that ubiquitous expression of rae28 could reverse the cardiac anomalies in rae28 Ϫ/Ϫ , whereas cardiomyocyte-specific expression of rae28 could not, suggesting that rae28 is involved in cardiac morphogenesis through a noncardiomyocyte pathway. Interestingly, however, cardiomyocyte-specific overexpression of rae28 caused dilated cardiomyopathy, which was associated with cardiomyocyte apoptosis, abnormal myofibrils, and severe heart failure. Cardiac expression of rae28 was predominant in the early embryonic stage, whereas that of the other PcG members was relatively constitutive. Because rae28 forms multimeric complexes with other PcG proteins in the nucleus, it is presumed that constitutive cardiomyocyte-specific rae28 overexpression impaired authentic PcG functions in the heart. rae28-induced dilated cardiomyopathy may thus provide a clue for clarifying the direct role of PcG in the maintenance of cardiomyocytes. (Lab Invest 2002, 82:375-385).

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Section: Figurementioning

confidence: 99%

Overexpression of Polycomb-Group Gene rae28 in Cardiomyocytes Does Not Complement Abnormal Cardiac Morphogenesis in Mice Lacking rae28 But Causes Dilated Cardiomyopathy

Koga

Kaji

Nishii

et al. 2002

Laboratory Investigation

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“…Although genes encoding sarcomeric proteins were traditionally considered to be involved in hypertrophic cardiomyopathy, 17 since 1998 it has also been known that mutations in these genes can cause IDC. 18 Thus, mutations in the genes coding for the a-and b-myosin heavy chains, 19 a-cardiac actin, 18 a-tropomyosin, 20 troponin T, 21 troponin I, 22 troponin C, 23 titin, 24 myosin-binding protein C 25 and telethonin 10 have been shown to cause IDC.…”

Section: Introductionmentioning

confidence: 99%

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

et al. 2009

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We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.

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“…Among these factors, it is estimated that heritable gene mutations account for 25-30% of cases (4). The first thin filament-associated DCM mutation was described in the cardiac actin gene (6). Subsequently, mutations were found in other sarcomeric proteins, including ␤-myosin heavy chain, cardiac myosin binding protein C, titin, ␣-Tm, and cardiac TnT (7).…”

mentioning

confidence: 99%

Different Functional Properties of Troponin T Mutants That Cause Dilated Cardiomyopathy

Venkatraman

Harada

Gomes

et al. 2003

Journal of Biological Chemistry

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The effects of Troponin T (TnT) mutants R141W and ⌬K210, the only two currently known mutations in TnT that cause dilated cardiomyopathy(DCM) independent of familial hypertrophic cardiomyopathy (FHC), and TnT-K273E, a mutation that leads to a progression from FHC to DCM, were investigated. Studies on the Ca 2؉ sensitivity of force development in porcine cardiac fibers demonstrated that TnT-⌬K210 caused a significant decrease in Ca 2؉ sensitivity, whereas the TnT-R141W did not result in any change in Ca 2؉ sensitivity when compared with human cardiac wild-type TnT (HCWTnT). TnT-⌬K210 also caused a decrease in maximal force when compared with HCWTnT and TnT-R141W. In addition, the TnT-⌬K210 mutant decreased maximal ATPase activity in the presence of Ca 2؉ . However, the TnT-K273E mutation caused a significant increase in Ca 2؉ sensitivity but behaved similarly to HCWTnT in actomyosin activation assays. Inhibition of ATPase activity in reconstituted actin-activated myosin ATPase assays was similar for all three TnT mutants and HCWTnT. Additionally, circular dichroism studies suggest that the secondary structure of all three TnT mutants was similar to that of the HCWTnT. These results suggest that a rightward shift in Ca 2؉ sensitivity is not the only determinant for the phenotype of DCM.

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Actin Mutations in Dilated Cardiomyopathy, a Heritable Form of Heart Failure

Cited by 607 publications

References 20 publications

Overexpression of Polycomb-Group Gene rae28 in Cardiomyocytes Does Not Complement Abnormal Cardiac Morphogenesis in Mice Lacking rae28 But Causes Dilated Cardiomyopathy

Overexpression of Polycomb-Group Gene rae28 in Cardiomyocytes Does Not Complement Abnormal Cardiac Morphogenesis in Mice Lacking rae28 But Causes Dilated Cardiomyopathy

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

Different Functional Properties of Troponin T Mutants That Cause Dilated Cardiomyopathy

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