Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences
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 homeo...
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| Veröffentlicht in: | Journal of the neurological sciences 2004-12, Vol.227 (1), p.27-33 |
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| creator | Wang, Xin-Sheng Lee, Sang Simmons, Zachary Boyer, Philip Scott, Kevin Liu, Wenlei Connor, James |
| description | 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 (
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| doi_str_mv | 10.1016/j.jns.2004.08.003 |
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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.</description><identifier>ISSN: 0022-510X</identifier><identifier>EISSN: 1878-5883</identifier><identifier>DOI: 10.1016/j.jns.2004.08.003</identifier><identifier>PMID: 15546588</identifier><identifier>CODEN: JNSCAG</identifier><language>eng</language><publisher>Shannon: Elsevier B.V</publisher><subject>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</subject><ispartof>Journal of the neurological sciences, 2004-12, Vol.227 (1), p.27-33</ispartof><rights>2004 Elsevier B.V.</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-ff02c28a04bb4b9a67601a264826d635f9665be1c84aa9cf4c73f14b97e8c9f73</citedby><cites>FETCH-LOGICAL-c445t-ff02c28a04bb4b9a67601a264826d635f9665be1c84aa9cf4c73f14b97e8c9f73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0022510X04002722$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16291855$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15546588$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Xin-Sheng</creatorcontrib><creatorcontrib>Lee, Sang</creatorcontrib><creatorcontrib>Simmons, Zachary</creatorcontrib><creatorcontrib>Boyer, Philip</creatorcontrib><creatorcontrib>Scott, Kevin</creatorcontrib><creatorcontrib>Liu, Wenlei</creatorcontrib><creatorcontrib>Connor, James</creatorcontrib><title>Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences</title><title>Journal of the neurological sciences</title><addtitle>J Neurol Sci</addtitle><description>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.</description><subject>Age of Onset</subject><subject>Amino Acids - genetics</subject><subject>Amyotrophic Lateral Sclerosis - blood</subject><subject>Amyotrophic Lateral Sclerosis - epidemiology</subject><subject>Amyotrophic Lateral Sclerosis - genetics</subject><subject>Amyotrophic Lateral Sclerosis - metabolism</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western - methods</subject><subject>Case-Control Studies</subject><subject>Cell Line, Tumor</subject><subject>Cytoskeletal Proteins - genetics</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>DNA Mutational Analysis - methods</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>Genotype</subject><subject>Hemochromatosis Protein</subject><subject>Hfe mutation</subject><subject>Histocompatibility Antigens Class I - genetics</subject><subject>Histocompatibility Antigens Class I - metabolism</subject><subject>Humans</subject><subject>Incidence</subject><subject>Iron</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Middle Aged</subject><subject>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</subject><subject>Mutation - genetics</subject><subject>Neuroblastoma</subject><subject>Neurology</subject><subject>Oxidative stress</subject><subject>Retrospective Studies</subject><subject>Reverse Transcriptase Polymerase Chain Reaction - methods</subject><subject>RNA, Messenger</subject><subject>SOD1</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase - metabolism</subject><subject>Transfection - methods</subject><issn>0022-510X</issn><issn>1878-5883</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1q3TAQRkVoSW7TPkA3RZt2Z3dkS7JMVyW0TSDQTQPZibE8IjL-uZXsQt4-MvdCdl0JRme-mTmMfRRQChD661AOcyorAFmCKQHqC3YQpjGFMqZ-ww4AVVUoAY9X7F1KAwBoY9pLdiWUkjpDBzbczS4SJup5mF3oaXbEF8_XJ-K3nvi0rbiGZc6_HKfnZY3L8Sk4PuJKEUee3EhxSSFxnHseaa_33NE4biNG7pY50d9tT03v2VuPY6IP5_eaPfz88efmtrj__evu5vt94aRUa-E9VK4yCLLrZNeibjQIrLQ0le51rXyrtepIOCMRW-ela2ovMtmQca1v6mv25ZR7jEsenVY7hbRvhDMtW7K6AdNKbTIoTqDLF6RI3h5jmDA-WwF2F2wHmwXbXbAFY7Pg3PPpHL51E_WvHWejGfh8BjA5HH3ErDW9crpqhVEqc99OHGUV_wJFm1zYPfUhklttv4T_rPECIlKadg</recordid><startdate>20041215</startdate><enddate>20041215</enddate><creator>Wang, Xin-Sheng</creator><creator>Lee, Sang</creator><creator>Simmons, Zachary</creator><creator>Boyer, Philip</creator><creator>Scott, Kevin</creator><creator>Liu, Wenlei</creator><creator>Connor, James</creator><general>Elsevier B.V</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20041215</creationdate><title>Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences</title><author>Wang, Xin-Sheng ; Lee, Sang ; Simmons, Zachary ; Boyer, Philip ; Scott, Kevin ; Liu, Wenlei ; Connor, James</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-ff02c28a04bb4b9a67601a264826d635f9665be1c84aa9cf4c73f14b97e8c9f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Age of Onset</topic><topic>Amino Acids - genetics</topic><topic>Amyotrophic Lateral Sclerosis - blood</topic><topic>Amyotrophic Lateral Sclerosis - epidemiology</topic><topic>Amyotrophic Lateral Sclerosis - genetics</topic><topic>Amyotrophic Lateral Sclerosis - metabolism</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western - methods</topic><topic>Case-Control Studies</topic><topic>Cell Line, Tumor</topic><topic>Cytoskeletal Proteins - genetics</topic><topic>Cytoskeletal Proteins - metabolism</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>DNA Mutational Analysis - methods</topic><topic>Female</topic><topic>Gene Frequency</topic><topic>Genotype</topic><topic>Hemochromatosis Protein</topic><topic>Hfe mutation</topic><topic>Histocompatibility Antigens Class I - genetics</topic><topic>Histocompatibility Antigens Class I - metabolism</topic><topic>Humans</topic><topic>Incidence</topic><topic>Iron</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Middle Aged</topic><topic>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</topic><topic>Mutation - genetics</topic><topic>Neuroblastoma</topic><topic>Neurology</topic><topic>Oxidative stress</topic><topic>Retrospective Studies</topic><topic>Reverse Transcriptase Polymerase Chain Reaction - methods</topic><topic>RNA, Messenger</topic><topic>SOD1</topic><topic>Superoxide Dismutase - genetics</topic><topic>Superoxide Dismutase - metabolism</topic><topic>Transfection - methods</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Xin-Sheng</creatorcontrib><creatorcontrib>Lee, Sang</creatorcontrib><creatorcontrib>Simmons, Zachary</creatorcontrib><creatorcontrib>Boyer, Philip</creatorcontrib><creatorcontrib>Scott, Kevin</creatorcontrib><creatorcontrib>Liu, Wenlei</creatorcontrib><creatorcontrib>Connor, James</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of the neurological sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Xin-Sheng</au><au>Lee, Sang</au><au>Simmons, Zachary</au><au>Boyer, Philip</au><au>Scott, Kevin</au><au>Liu, Wenlei</au><au>Connor, James</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences</atitle><jtitle>Journal of the neurological sciences</jtitle><addtitle>J Neurol Sci</addtitle><date>2004-12-15</date><risdate>2004</risdate><volume>227</volume><issue>1</issue><spage>27</spage><epage>33</epage><pages>27-33</pages><issn>0022-510X</issn><eissn>1878-5883</eissn><coden>JNSCAG</coden><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.</abstract><cop>Shannon</cop><pub>Elsevier B.V</pub><pmid>15546588</pmid><doi>10.1016/j.jns.2004.08.003</doi><tpages>7</tpages></addata></record> |
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| 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 |
| title | Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences |
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