Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences

• Published in: Journal of the neurological sciences Vol. 227; no. 1; pp. 27 - 33
• Main Authors: Wang, Xin-Sheng, Lee, Sang, Simmons, Zachary, Boyer, Philip, Scott, Kevin, Liu, Wenlei, Connor, James
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 15.12.2004; Elsevier Science
• Subjects: Age of Onset; Amino Acids - genetics; Amyotrophic Lateral Sclerosis - blood; Amyotrophic Lateral Sclerosis - epidemiology; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Biological and medical sciences; Blotting, Western - methods; Case-Control Studies; Cell Line, Tumor; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Mutational Analysis - methods; Female; Gene Frequency; Genotype; Hemochromatosis Protein; Hfe mutation; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Humans; Incidence; Iron; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Mutation - genetics; Neuroblastoma; Neurology; Oxidative stress; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger; SOD1; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Transfection - methods; PBS; Oxidative stress; ABC; AD; SDS; HFE; HRP; ALS; CNS; SOD; Iron; DFO; NGF; SOD1; PC12; OD; ROS; Hfe mutation; ID; AEC; Nervous system diseases; Central nervous system disease; Amyotrophic lateral sclerosis; Degenerative disease; Mutation; Spinal cord disease; Incidence
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/j.jns.2004.08.003

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.