Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure

Waldmüller, Stephan; Erdmann, J.; Binner, Priska; Gelbrich, Götz; Pankuweit, Sabine; Geier, Christian; Timmermann, Bernd; Haremza, Janine; Perrot, Andreas; Scheer, Steffen; Wachter, Rolf; Schulze‐Waltrup, Norbert; Dermintzoglou, Anastassia; Schönberger, Jost; Zeh, Wolfgang; Jurmann, B.; Brodherr, Turgut; Börgel, Jan; Farr, Martin; Milting, Hendrik; Blankenfeldt, Wulf; Reinhardt, Richard; Özcelik, Cemil; Osterziel, Karl‐Josef; Loeffler, Markus; Maisch, Bernhard; Regitz‐Zagrosek, Vera; Schunkert, Heribert; Scheffold, Thomas

doi:10.1093/eurjhf/hfr074

Cited by 79 publications

(83 citation statements)

References 24 publications

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“…Younger age at presentation in carriers of sarcomere protein gene mutations is a common finding in many studies 37 41 48 – 51. The presence of multiple sarcomere gene mutations (double or triple heterozygosity, compound heterozygosity or homozygosity) was associated with a younger age compared to a single mutation or to the absence of mutations in a single report 41.…”

Section: Demographic Characteristics and Family Historymentioning

confidence: 95%

A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations

Lopes

Rahman

Elliott

2013

Heart

177

105

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Section: Demographic Characteristics and Family Historymentioning

confidence: 95%

A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations

Lopes

Rahman

Elliott

2013

Heart

177

105

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“…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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“…27,28) However, recent clinical reports have shown that genes affected by mutations, such as MYH7, may determine the magnitude of structural and functional alterations in both HcM and dcM, and that other factors, such as environmental factors that stimulate the expression of HcM phenotypes, can lead to dcM phenotypes where both right and left ventricles are affected, leading to heart failure. 29,30) Thus, in some cases, dcM may occur secondarily to a progressed and end-stage HcM. 29,30) Left ventricular noncompaction cardiomyopathy that is caused by a MYH7 missense mutation such as A1766T 31) is another disease that should be recognized as characteristic in dcM patients.…”

Section: Sarcomere Proteins As a Cause Of Dcmmentioning

confidence: 99%

“…29,30) Thus, in some cases, dcM may occur secondarily to a progressed and end-stage HcM. 29,30) Left ventricular noncompaction cardiomyopathy that is caused by a MYH7 missense mutation such as A1766T 31) is another disease that should be recognized as characteristic in dcM patients. 32,33) This disease is a myocardial disorder thought to occur as a result of arrested embryogenesis and is characterized by a spongy morphological appearance of the myocardium.…”

Section: Sarcomere Proteins As a Cause Of Dcmmentioning

confidence: 99%

Dilated Cardiomyopathy: A Disease of the Myocardium

Sanbe

2013

Biological & Pharmaceutical Bulletin

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Cardiomyopathies are defined as cardiac diseases of the myocardium with associated cardiac dysfunction. They are cardiac diseases in which heart muscle disease and/or measurable deterioration of cardiac muscle function occurs due to various causes, such as genetic and sporadic mutations of muscle proteins, as well as external factors such as hypertension, ischemia, and inflammation. In 1995, the WHO/International Society and Federation of Cardiology (ISFC) classified primary cardiomyopathy caused by intrinsic factors into five groups according to the dominant pathophysiology: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and unclassified cardiomyopathy. Among these cardiomyopathies, DCM is the most prevalent and the most common reason for cardiac transplantation in adults and children. Many recent findings indicate that genetic and sporadic mutations of a number of muscle proteins, such as myofibrillar, structural, and Ca 2+ regulating proteins, can cause DCM. In such cases, certain mutations often induce DCM with cardiac arrhythmia that is recognized as a potential trigger of sudden cardiac death. Thus, effective prognostic determination and appropriate cardiac care depend on accurate molecular and genetic diagnoses.

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Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure

Abstract: A large clinical-genetic study has unravelled novel genotype-to-phenotype correlations in HCM and DCM which warrant future investigation of both the underlying mechanisms and the prognostic use.

Cited by 79 publications

References 24 publications

A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations

A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations

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

Dilated Cardiomyopathy: A Disease of the Myocardium

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