title: Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences.
abstract: The etiology of amyotrophic lateral sclerosis (ALS) is unknown. The presence of mutations in the superoxide dismutase gene (SOD1) has led to theories regarding a role for oxidative stress in the pathogenesis of this disease. A primary cause of oxidative stress is perturbations in cellular iron homeostasis. Cellular iron mismanagement and oxidative stress are associated with a number of neurodegenerative diseases. One mechanism by which cells fail to properly regulate their iron status is through a mutation in the Hfe gene. Mutations in the Hfe gene are associated with the iron overload disease, hemochromatosis. In the current study, 31% of patients with sporadic ALS carried a mutation in the Hfe gene, compared to only 14% of patients without identifiable neuromuscular disease, or with neuromuscular diseases other than ALS (p<0.005). To determine the cellular consequences of carrying an Hfe mutation, a human neuronal cell line was transfected with genes carrying the Hfe mutation. The presence of the Hfe mutation disrupted expression of tubulin and actin at the protein levels potentially consistent with the disruption of axonal transport seen in ALS and was also associated with a decrease in CuZnSOD1 expression. These data provide compelling evidence for a role for the Hfe mutation in etiopathogenesis of ALS and warrant further investigation.
authors.affiliation: Department of Neurosurgery, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Wang
authors.forename: Sang
authors.initials: S
authors.lastname: Lee
authors.forename: Zachary
authors.initials: Z
authors.lastname: Simmons
authors.forename: Philip
authors.initials: P
authors.lastname: Boyer
authors.forename: Kevin
authors.initials: K
authors.lastname: Scott
authors.forename: Wenlei
authors.initials: W
authors.lastname: Liu
authors.forename: James
authors.initials: J
authors.lastname: Connor
mesh_terms: D017668:Age of Onset; D000596:Amino Acids / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015994:Incidence; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma; D012333:RNA, Messenger; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D000596:Amino Acids; D003598:Cytoskeletal Proteins; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D012333:RNA, Messenger; D013482:Superoxide Dismutase