Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance.
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.
Mochel
Fanny
F
Developmental and Metabolic Neurology Branch, NINDS, NIH, Bethesda, MD 20892, USA. mochelf@ninds.nih.gov
Knight
Melanie A
MA
Tong
Wing-Hang
WH
Hernandez
Dena
D
Ayyad
Karen
K
Taivassalo
Tanja
T
Andersen
Peter M
PM
Singleton
Andrew
A
Rouault
Tracey A
TA
Fischbeck
Kenneth H
KH
Haller
Ronald G
RG
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
C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D013385:Succinate Dehydrogenase; D000154:Aconitate Hydratase