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Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy.

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Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. / Friedrich, Felix; Wilding, Brendan R; Reischmann, Silke; Crocini, Claudia; Lang, Patrick; Charron, Philippe; Müller, Oliver J; McGrath, Meagan J; Vollert, Ingra; Hansen, Arne; Linke, Wolfgang A; Hengstenberg, Christian; Bonne, Gisèle; Morner, Stellan; Wichter, Thomas; Madeira, Hugo; Arbustini, Eloisa; Eschenhagen, Thomas; Mitchell, Christina A; Isnard, Richard; Carrier, Lucie.

in: HUM MOL GENET, Jahrgang 21, Nr. 14, 14, 2012, S. 3237-3254.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Friedrich, F, Wilding, BR, Reischmann, S, Crocini, C, Lang, P, Charron, P, Müller, OJ, McGrath, MJ, Vollert, I, Hansen, A, Linke, WA, Hengstenberg, C, Bonne, G, Morner, S, Wichter, T, Madeira, H, Arbustini, E, Eschenhagen, T, Mitchell, CA, Isnard, R & Carrier, L 2012, 'Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy.', HUM MOL GENET, Jg. 21, Nr. 14, 14, S. 3237-3254. <http://www.ncbi.nlm.nih.gov/pubmed/22523091?dopt=Citation>

APA

Friedrich, F., Wilding, B. R., Reischmann, S., Crocini, C., Lang, P., Charron, P., Müller, O. J., McGrath, M. J., Vollert, I., Hansen, A., Linke, W. A., Hengstenberg, C., Bonne, G., Morner, S., Wichter, T., Madeira, H., Arbustini, E., Eschenhagen, T., Mitchell, C. A., ... Carrier, L. (2012). Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. HUM MOL GENET, 21(14), 3237-3254. [14]. http://www.ncbi.nlm.nih.gov/pubmed/22523091?dopt=Citation

Vancouver

Friedrich F, Wilding BR, Reischmann S, Crocini C, Lang P, Charron P et al. Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. HUM MOL GENET. 2012;21(14):3237-3254. 14.

Bibtex

@article{bb8b99a4040a453c924f02b3e48e2456,
title = "Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy.",
abstract = "Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.",
keywords = "Adult, Animals, Humans, Male, Aged, Middle Aged, Adolescent, Young Adult, Child, Cells, Cultured, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Case-Control Studies, Cardiomyopathy, Hypertrophic/*genetics/metabolism, Intracellular Signaling Peptides and Proteins/*genetics/metabolism, LIM Domain Proteins/*genetics/metabolism, Muscle Proteins/*genetics/metabolism, Myocytes, Cardiac/metabolism, Adult, Animals, Humans, Male, Aged, Middle Aged, Adolescent, Young Adult, Child, Cells, Cultured, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Case-Control Studies, Cardiomyopathy, Hypertrophic/*genetics/metabolism, Intracellular Signaling Peptides and Proteins/*genetics/metabolism, LIM Domain Proteins/*genetics/metabolism, Muscle Proteins/*genetics/metabolism, Myocytes, Cardiac/metabolism",
author = "Felix Friedrich and Wilding, {Brendan R} and Silke Reischmann and Claudia Crocini and Patrick Lang and Philippe Charron and M{\"u}ller, {Oliver J} and McGrath, {Meagan J} and Ingra Vollert and Arne Hansen and Linke, {Wolfgang A} and Christian Hengstenberg and Gis{\`e}le Bonne and Stellan Morner and Thomas Wichter and Hugo Madeira and Eloisa Arbustini and Thomas Eschenhagen and Mitchell, {Christina A} and Richard Isnard and Lucie Carrier",
year = "2012",
language = "English",
volume = "21",
pages = "3237--3254",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "14",

}

RIS

TY - JOUR

T1 - Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy.

AU - Friedrich, Felix

AU - Wilding, Brendan R

AU - Reischmann, Silke

AU - Crocini, Claudia

AU - Lang, Patrick

AU - Charron, Philippe

AU - Müller, Oliver J

AU - McGrath, Meagan J

AU - Vollert, Ingra

AU - Hansen, Arne

AU - Linke, Wolfgang A

AU - Hengstenberg, Christian

AU - Bonne, Gisèle

AU - Morner, Stellan

AU - Wichter, Thomas

AU - Madeira, Hugo

AU - Arbustini, Eloisa

AU - Eschenhagen, Thomas

AU - Mitchell, Christina A

AU - Isnard, Richard

AU - Carrier, Lucie

PY - 2012

Y1 - 2012

N2 - Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.

AB - Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.

KW - Adult

KW - Animals

KW - Humans

KW - Male

KW - Aged

KW - Middle Aged

KW - Adolescent

KW - Young Adult

KW - Child

KW - Cells, Cultured

KW - Mice

KW - Mice, Inbred C57BL

KW - Mutation

KW - Pedigree

KW - Case-Control Studies

KW - Cardiomyopathy, Hypertrophic/genetics/metabolism

KW - Intracellular Signaling Peptides and Proteins/genetics/metabolism

KW - LIM Domain Proteins/genetics/metabolism

KW - Muscle Proteins/genetics/metabolism

KW - Myocytes, Cardiac/metabolism

KW - Adult

KW - Animals

KW - Humans

KW - Male

KW - Aged

KW - Middle Aged

KW - Adolescent

KW - Young Adult

KW - Child

KW - Cells, Cultured

KW - Mice

KW - Mice, Inbred C57BL

KW - Mutation

KW - Pedigree

KW - Case-Control Studies

KW - Cardiomyopathy, Hypertrophic/genetics/metabolism

KW - Intracellular Signaling Peptides and Proteins/genetics/metabolism

KW - LIM Domain Proteins/genetics/metabolism

KW - Muscle Proteins/genetics/metabolism

KW - Myocytes, Cardiac/metabolism

M3 - SCORING: Journal article

VL - 21

SP - 3237

EP - 3254

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 14

M1 - 14

ER -