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.
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Felix W
authors.initials: FW
authors.lastname: Friedrich
authors.forename: Brendan R
authors.initials: BR
authors.lastname: Wilding
authors.forename: Silke
authors.initials: S
authors.lastname: Reischmann
authors.forename: Claudia
authors.initials: C
authors.lastname: Crocini
authors.forename: Patrick
authors.initials: P
authors.lastname: Lang
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: McGrath
authors.forename: Ingra
authors.initials: I
authors.lastname: Vollert
authors.forename: Arne
authors.initials: A
authors.lastname: Hansen
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.forename: Stellan
authors.initials: S
authors.lastname: Morner
authors.forename: Thomas
authors.initials: T
authors.lastname: Wichter
authors.forename: Hugo
authors.initials: H
authors.lastname: Madeira
authors.forename: Eloisa
authors.initials: E
authors.lastname: Arbustini
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
authors.forename: Richard
authors.initials: R
authors.lastname: Isnard
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D010375:Pedigree; D055815:Young Adult
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins