Molecular and functional characterization of a human frataxin mutation found in hypertrophic cardiomyopathy

Sara L. Van Driest, Oleksandr Gakh, Steve R. Ommen, Grazia Isaya, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Hypertrophic cardiomyopathy is associated with marked genetic and phenotypic heterogeneity. Pathogenic mutations in the 10 hypertrophic cardiomyopathy-associated sarcomeric genes cause autosomal dominant disease as a rule, although recessive disease has been reported. Cardiac hypertrophy is also a hallmark of Friedreich ataxia, an autosomal recessive disease caused by deficiency of the mitochondrial protein frataxin. We hypothesized that heterozygous mutations in frataxin may mimic or modify hypertrophic cardiomyopathy. Using DHPLC and DNA sequencing, we identified the novel R40C-frataxin mutation in a patient who also harbored a previously reported R810H-myosin binding protein C mutation. The R810H mutation is reported to cause hypertrophic cardiomyopathy only in the setting of homozygosity or compound heterozygosity with another sarcomeric mutation. Site-directed mutagenesis and in vitro and in vivo analysis enabled functional characterization of the mutant frataxin protein. R40C-frataxin protein is not cleaved to the mature form in vitro and shows delayed kinetics of cleavage by isolated mouse mitochondria. Yeast cells expressing R40C-frataxin demonstrated increased sensitivity to oxidative stress and abnormal accumulation of precursor frataxin protein. These data indicate that frataxin deficiency may have contributed to this patient's particular phenotype. Furthermore, these findings suggest that mutations altering myocyte energetics may act in synergy with sarcomeric mutations to cause hypertrophic cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)280-285
Number of pages6
JournalMolecular genetics and metabolism
Issue number4
StatePublished - Aug 2005


  • Frataxin
  • Friedreich ataxia
  • Genetics
  • Hypertrophic cardiomyopathy
  • Myosin binding protein C

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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