Abstract 904: Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy

Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 not only reduces contractility but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results help link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.

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Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy

10.1101/555391 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sarah R. Clippinger ◽

Paige E. Cloonan ◽

Lina Greenberg ◽

Melanie Ernst ◽

W. Tom Stump ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Troponin T ◽

Heart Tissue ◽

Substrate Stiffness ◽

Cellular Organization ◽

Sarcomeric Proteins ◽

Critical Gap ◽

Cellular Hypertrophy ◽

Familial Dilated Cardiomyopathy ◽

Cellular Phenotypes

AbstractFamilial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 not only reduces contractility, but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.

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389 Mutations in troponin and tropomyosin that cause familial dilated cardiomyopathy decrease crossbridge cycling speed and Ca-sensitivity

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(05)80233-4 ◽

2005 ◽

Vol 4 (1) ◽

pp. 86-86

Keyword(s):

Dilated Cardiomyopathy ◽

Familial Dilated Cardiomyopathy ◽

Cycling Speed ◽

Ca Sensitivity

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Association of Polymorphisms of Manganese Superoxide Dismutase and Plasma Platelet-activating Factor Acetylhydrolase Genes With Genetic Susceptibility to Non-familial Dilated Cardiomyopathy

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(97)85334-x ◽

1998 ◽

Vol 31 (2) ◽

pp. 374A

Author(s):

S Ichihara

Keyword(s):

Superoxide Dismutase ◽

Dilated Cardiomyopathy ◽

Genetic Susceptibility ◽

Manganese Superoxide Dismutase ◽

Platelet Activating Factor ◽

Familial Dilated Cardiomyopathy ◽

Platelet Activating Factor Acetylhydrolase ◽

Manganese Superoxide

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A case of familial dilated cardiomyopathy

Ultraschall in der Medizin - European Journal of Ultrasound ◽

10.1055/s-0033-1354991 ◽

2013 ◽

Vol 34 (S 01) ◽

Author(s):

P Hutsteiner ◽

N Jenewein ◽

J Christ ◽

O Ortmann ◽

U Germer

Keyword(s):

Dilated Cardiomyopathy ◽

Familial Dilated Cardiomyopathy

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Localization of a Gene Responsible for Familial Dilated Cardiomyopathy to Chromosome 1q32

Circulation ◽

10.1161/01.cir.92.12.3387 ◽

1995 ◽

Vol 92 (12) ◽

pp. 3387-3389 ◽

Cited By ~ 91

Author(s):

Jean-Bernard Durand ◽

Linda L. Bachinski ◽

Lisa C. Bieling ◽

Grazyna Z. Czernuszewicz ◽

Antoine B. Abchee ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Familial Dilated Cardiomyopathy

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Reassessment of Gene-Elusive Familial Dilated Cardiomyopathy Leading to the Discovery of a Homozygous AARS2 Variant—The Importance of Regular Reassessment of Genetic Findings

Cardiogenetics ◽

10.3390/cardiogenetics11030013 ◽

2021 ◽

Vol 11 (3) ◽

pp. 122-128

Author(s):

Priya Bhardwaj ◽

Christoffer Rasmus Vissing ◽

Niels Kjær Stampe ◽

Kasper Rossing ◽

Alex Hørby Christensen ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Genetic Screening ◽

Sanger Sequencing ◽

Mitochondrial Protein ◽

Trna Synthetase ◽

Familial Dilated Cardiomyopathy ◽

Pathogenic Variants ◽

Case Summary ◽

Heterozygous Carriers ◽

Important Enzyme

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

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