Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance

Am J Hum Genet. 2008 Mar;82(3):652-60. doi: 10.1016/j.ajhg.2007.12.012. Epub 2008 Feb 14.


A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitate Hydratase / deficiency
  • Adult
  • Aged
  • Amino Acid Sequence
  • Base Sequence
  • DNA Mutational Analysis
  • Exercise Tolerance / genetics*
  • Homozygote
  • Humans
  • Iron-Sulfur Proteins / genetics*
  • Mitochondria / enzymology
  • Mitochondrial Myopathies / enzymology
  • Mitochondrial Myopathies / genetics*
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Polymorphism, Single Nucleotide
  • RNA Splice Sites / genetics*
  • RNA, Messenger / metabolism
  • Succinate Dehydrogenase / deficiency
  • Sweden


  • ISCU protein, human
  • Iron-Sulfur Proteins
  • RNA Splice Sites
  • RNA, Messenger
  • Succinate Dehydrogenase
  • Aconitate Hydratase

Associated data

  • GENBANK/EU329002
  • GENBANK/EU334585