Dilated cardiomyopathy

Weintraub, Robert G.; Semsarian, Christopher; Macdonald, P.

doi:10.1016/s0140-6736(16)31713-5

Cited by 497 publications

(514 citation statements)

References 165 publications

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“…The first human mutation identified was R9C (PLN R9C ), located in domain Ia of the regulatory region[20]. This autosomal dominant, missense mutation at nucleotide 25 causes the typical DCM phenotype, with a severe dilation of the left ventricle and decreased contractile function of the heart muscle[21]. The later sequencing of R9H and R9L mutations in DCM patients further emphasized the importance of PLN’s position 9 for SERCA regulation [22].…”

Section: Introductionmentioning

confidence: 99%

Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers

Nelson

Gopinath

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Approximately, 70% of the Ca ion transport into the sarcoplasmic reticulum is catalyzed by the sarcoplasmic reticulum Ca-ATPase (SERCA), whose activity is endogenously regulated by phospholamban (PLN). PLN comprises a TM inhibitory region and a cytoplasmic regulatory region that harbors a consensus sequence for cAMP-dependent protein kinase (PKA). The inhibitory region binds the ATPase, reducing its apparent Ca binding affinity. β-adrenergic stimulation activates PKA, which phosphorylates PLN at Ser 16, reversing its inhibitory function. Mutations and post-translational modifications of PLN may lead to dilated cardiomyopathy (DCM) and heart failure. PLN's cytoplasmic region interconverts between a membrane-associated T state and a membrane-detached R state. The importance of these structural transitions on SERCA regulation is emerging, but the effects of natural occurring mutations and their relevance to the progression of heart disease are unclear. Here we use solid-state NMR spectroscopy to investigate the structural dynamics of two lethal PLN mutations, R9C and R25C, which lead to DCM. We found that the R25C mutant enhances the dynamics of PLN and shifts the conformational equilibrium toward the R state confirmation, whereas the R9C mutant drives the amphipathic cytoplasmic domain toward the membrane-associate state, enriching the T state population. The changes in membrane interactions caused by these mutations may explain the aberrant regulation of SERCA.

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Section: Introductionmentioning

confidence: 99%

Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers

Nelson

Gopinath

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Here, two scenarios can be thought of cases with a cardiomyopathy diagnosis preceding death and cases with a sudden cardiac death (ie, no lifetime cardiomyopathy diagnosis). Dilated cardiomyopathy in live patients can be indicated by rather unspecific symptoms, such as abdominal pain, fatigue or nausea, but formal diagnosis gets only confirmed via echocardiography, MRI and/or histological analyses 20. For individuals who died from a sudden cardiac death, an analogue diagnostic workup may not be feasible.…”

Section: Discussionmentioning

confidence: 99%

National, regional and global mortality due to alcoholic cardiomyopathy in 2015

Manthey¹,

Probst²,

Rylett³

et al. 2018

Heart

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The variation of ACM mortality burden is greater than for other alcohol-attributable diseases, and partly may be the result of stigma and lack of detection. Misclassification of ACM fatalities is a systematic phenomenon, which may be caused by low resources, lacking standards and stigma associated with alcohol-use disorders. Clinical management may be improved by including routine alcohol assessments. This could contribute to decrease misclassifications and to provide the best available treatment for affected patients.

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“…The typical symptoms of DCM include cardiac dilation, systolic dysfunction, and, in particular, left ventricular enlargement or dilatation [McNally and Mestroni, 2017;Weintraub et al, 2017]. According to the Olmsted County studies, the prevalence of DCM is likely to be 1 in 250 individuals [Codd et al, 1989;Hershberger et al, 2013].…”

confidence: 99%

Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

Fan

Huang

Jin

et al. 2019

Cytogenet Genome Res

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Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.

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Dilated cardiomyopathy

Cited by 497 publications

References 165 publications

Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers

Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers

National, regional and global mortality due to alcoholic cardiomyopathy in 2015

Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

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