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, Vol. 21, No. 14, 14, 2012, p. 3237-3254.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -