Sarcomere Protein Gene Mutations in Hypertrophic Cardiomyopathy of the Elderly

Niimura, Hideshi; Patton, Kristen K.; McKenna, William J.; Soults, J A; Maron, Barry J.; Seidman, Jonathan G.; Seidman, Christine E.

doi:10.1161/hc0402.102990

Cited by 302 publications

(231 citation statements)

References 33 publications

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“…Although the latter variant has also been described as a polymorphism in two earlier studies, 29,30 the other two mutations have been described only as HCM-causing mutations, indicating phenotypic plasticity.…”

Section: Discussionmentioning

confidence: 91%

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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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Section: Discussionmentioning

confidence: 91%

“…29,30 It results in the replacement of a conserved charged arginine with neutral glutamine at residue 326 in the phosphorylatable MyBPC motif of cMyBPC. This charge change is likely to cause functional impairment.…”

Section: Phenotypic Description and Genotype Analysismentioning

confidence: 99%

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

et al. 2009

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“…Indeed, α-MHC mRNA and protein levels are markedly reduced in failing human hearts (16,17), and improvement of left-ventricular ejection fraction through β blocker therapy is associated with normalization of α-MHC expression (10). Additionally, a mutation in the human α-MHC gene was identified in association with hypertrophic cardiomyopathy (18), which demonstrates that, despite its low abundance, α-MHC is critical for normal heart function and further validates the hypothesis that MHC isoform switching plays a significant role in human heart failure.…”

Section: Transcriptional Remodeling Of the Hypertrophic And Failing Hmentioning

confidence: 99%

Toward transcriptional therapies for the failing heart: chemical screens to modulate genes

McKinsey¹,

Olson²

2005

J. Clin. Invest.

117

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In response to acute and chronic stresses, the heart frequently undergoes a remodeling process that is accompanied by myocyte hypertrophy, impaired contractility, and pump failure, often culminating in sudden death. The existence of redundant signaling pathways that trigger heart failure poses challenges for therapeutic intervention. Cardiac remodeling is associated with the activation of a pathological gene program that weakens cardiac performance. Thus, targeting the disease process at the level of gene expression represents a potentially powerful therapeutic approach. In this review, we describe strategies for normalizing gene expression in the failing heart with small molecules that control signal transduction pathways directed at transcription factors and associated chromatin-modifying enzymes.

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“…31 The present study focused on the prevalence and associated phenotype of specific mutations ascribed as benign, rather than comprehensive mutational analysis of an entire gene. Future studies involving a comprehensive analysis of MYBPC3 should confirm whether its present status as a benign HCM gene is maintained after examination of this large referral population of HCM.…”

Section: Study Limitationsmentioning

confidence: 99%

Prevalence and Severity of “Benign” Mutations in the β-Myosin Heavy Chain, Cardiac Troponin T, and α-Tropomyosin Genes in Hypertrophic Cardiomyopathy

et al. 2002

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Background-Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of ␤-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of ␣-tropomyosin (TPM1). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown. Methods and Results-A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and 1 adolescent requiring an orthotopic heart transplant. Conclusions-These findings demonstrate the rarity of specific mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course. (Circulation. 2002;106:3085-3090.)

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Sarcomere Protein Gene Mutations in Hypertrophic Cardiomyopathy of the Elderly

Cited by 302 publications

References 33 publications

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

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

Toward transcriptional therapies for the failing heart: chemical screens to modulate genes

Prevalence and Severity of “Benign” Mutations in the β-Myosin Heavy Chain, Cardiac Troponin T, and α-Tropomyosin Genes in Hypertrophic Cardiomyopathy

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