title: Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.
abstract: 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.
authors.affiliation: Developmental and Metabolic Neurology Branch, NINDS, NIH, Bethesda, MD 20892, USA. mochelf@ninds.nih.gov
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Knight
authors.forename: Wing-Hang
authors.initials: WH
authors.lastname: Tong
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Karen
authors.initials: K
authors.lastname: Ayyad
authors.forename: Tanja
authors.initials: T
authors.lastname: Taivassalo
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Rouault
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Haller
mesh_terms: D000154:Aconitate Hydratase / Q000172:deficiency; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017079:Exercise Tolerance / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000172:deficiency; D013548:Sweden
chemical_list: C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D013385:Succinate Dehydrogenase; D000154:Aconitate Hydratase