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

Felix W. Friedrich, Brendan R. Wilding, Silke Reischmann, Claudia Crocini, Patrick Lang, Philippe Charron, Oliver J. Müller, Meagan J. Mcgrath, Ingra Vollert, Arne Hansen, Wolfgang A. Linke, Christian Hengstenberg, Gisèle Bonne, Stellan Morner, Thomas Wichter, Hugo Madeira, Eloisa Arbustini, Thomas Eschenhagen, Christina A. Mitchell, Richard IsnardLucie Carrier

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numberdds157
Pages (from-to)3237-3254
Number of pages18
JournalHuman Molecular Genetics
Volume21
Issue number14
DOIs
Publication statusPublished - Jul 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Friedrich, F. W., 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. Human Molecular Genetics, 21(14), 3237-3254. [dds157]. https://doi.org/10.1093/hmg/dds157