A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase
Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease 1–4 . Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine m...
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| Veröffentlicht in: | Nature genetics 1995-05, Vol.10 (1), p.111-113 |
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| creator | Frosst, P Blom, H.J Milos, R Goyette, P Sheppard, C.A Matthews, R.G Boers, G.J.H den Heijer, M Kluijtmans, L.A.J van den Heuve, L.P Rozen, R |
| description | Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease
1–4
. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism
1,5–7
. 5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetra-hydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease
5,6
. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts;
in vitro
expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease. |
| doi_str_mv | 10.1038/ng0595-111 |
| format | Article |
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1–4
. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism
1,5–7
. 5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetra-hydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease
5,6
. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts;
in vitro
expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/ng0595-111</identifier><identifier>PMID: 7647779</identifier><identifier>CODEN: NGENEC</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>5,10-methylenetetrahydrofolate reductase ; Adult ; Agriculture ; Aminoacid disorders ; Animal Genetics and Genomics ; Base Sequence ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; DNA, Complementary ; Enzyme Stability ; Errors of metabolism ; Escherichia coli - metabolism ; Female ; Gene Function ; Homocysteine - metabolism ; Human Genetics ; Humans ; hyperhomocysteinemia ; Kidney - metabolism ; letter ; Liver - metabolism ; Lymphocytes - metabolism ; Male ; man ; Medical sciences ; Metabolic diseases ; Methylenetetrahydrofolate Reductase (NADPH2) ; Middle Aged ; Molecular Sequence Data ; MTHFR gene ; Mutagenesis, Site-Directed ; Mutation ; Oxidoreductases Acting on CH-NH Group Donors - deficiency ; Oxidoreductases Acting on CH-NH Group Donors - genetics ; Quebec ; Risk Factors ; Temperature ; vascular disease ; Vascular Diseases - epidemiology ; Vascular Diseases - genetics</subject><ispartof>Nature genetics, 1995-05, Vol.10 (1), p.111-113</ispartof><rights>Springer Nature America, Inc. 1995</rights><rights>1995 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c505t-83974cee33083620ed336af53eb2a9954d06a0124b0e783f292acd0ad8aeb31b3</citedby><cites>FETCH-LOGICAL-c505t-83974cee33083620ed336af53eb2a9954d06a0124b0e783f292acd0ad8aeb31b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2727,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3509404$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7647779$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Frosst, P</creatorcontrib><creatorcontrib>Blom, H.J</creatorcontrib><creatorcontrib>Milos, R</creatorcontrib><creatorcontrib>Goyette, P</creatorcontrib><creatorcontrib>Sheppard, C.A</creatorcontrib><creatorcontrib>Matthews, R.G</creatorcontrib><creatorcontrib>Boers, G.J.H</creatorcontrib><creatorcontrib>den Heijer, M</creatorcontrib><creatorcontrib>Kluijtmans, L.A.J</creatorcontrib><creatorcontrib>van den Heuve, L.P</creatorcontrib><creatorcontrib>Rozen, R</creatorcontrib><title>A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease
1–4
. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism
1,5–7
. 5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetra-hydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease
5,6
. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts;
in vitro
expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.</description><subject>5,10-methylenetetrahydrofolate reductase</subject><subject>Adult</subject><subject>Agriculture</subject><subject>Aminoacid disorders</subject><subject>Animal Genetics and Genomics</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>DNA, Complementary</subject><subject>Enzyme Stability</subject><subject>Errors of metabolism</subject><subject>Escherichia coli - metabolism</subject><subject>Female</subject><subject>Gene Function</subject><subject>Homocysteine - metabolism</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>hyperhomocysteinemia</subject><subject>Kidney - metabolism</subject><subject>letter</subject><subject>Liver - metabolism</subject><subject>Lymphocytes - metabolism</subject><subject>Male</subject><subject>man</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Methylenetetrahydrofolate Reductase (NADPH2)</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>MTHFR gene</subject><subject>Mutagenesis, Site-Directed</subject><subject>Mutation</subject><subject>Oxidoreductases Acting on CH-NH Group Donors - deficiency</subject><subject>Oxidoreductases Acting on CH-NH Group Donors - genetics</subject><subject>Quebec</subject><subject>Risk Factors</subject><subject>Temperature</subject><subject>vascular disease</subject><subject>Vascular Diseases - epidemiology</subject><subject>Vascular Diseases - genetics</subject><issn>1061-4036</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU1rFTEUhoMotVY37oUspAtl6skkmQ93pfgFBTd1PZxJztymziQ1yQj33zeXuVw3LkIOvE_eA08YeyvgSoDsPvkd6F5XQohn7Fxo1VSiFd3zMkMjKgWyeclepfQAIJSC7oydtY1q27Y_Z_6aG_TWWczEd-QpO8OjS7_5hCaHyKdy_mIy64yRW5cIE33myE1YluD5smbMrgyuzJTv9_Ohg3LE-72NYQrzoTiSXU0uL1-zFxPOid4c7wv26-uXu5vv1e3Pbz9urm8ro0HnqpN9qwyRlNDJpgayUjY4aUljjX2vlYUGQdRqBGo7OdV9jcYC2g5plGKUF-xy632M4c9KKQ-LS4bmGT2FNQ2iaWUvhS7ghw00MaQUaRoeo1sw7gcBw0HusMkditwCvzu2ruNC9oQebZb8_TEvwnCeInrj0gmTGnoFqmAfNyyVxO8oDg9hjb74-P9SvtEe8xrp1Pbv0-UTXDCb1g</recordid><startdate>19950501</startdate><enddate>19950501</enddate><creator>Frosst, P</creator><creator>Blom, H.J</creator><creator>Milos, R</creator><creator>Goyette, P</creator><creator>Sheppard, C.A</creator><creator>Matthews, R.G</creator><creator>Boers, G.J.H</creator><creator>den Heijer, M</creator><creator>Kluijtmans, L.A.J</creator><creator>van den Heuve, L.P</creator><creator>Rozen, R</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</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>7T3</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>19950501</creationdate><title>A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase</title><author>Frosst, P ; Blom, H.J ; Milos, R ; Goyette, P ; Sheppard, C.A ; Matthews, R.G ; Boers, G.J.H ; den Heijer, M ; Kluijtmans, L.A.J ; van den Heuve, L.P ; Rozen, R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c505t-83974cee33083620ed336af53eb2a9954d06a0124b0e783f292acd0ad8aeb31b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>5,10-methylenetetrahydrofolate reductase</topic><topic>Adult</topic><topic>Agriculture</topic><topic>Aminoacid disorders</topic><topic>Animal Genetics and Genomics</topic><topic>Base Sequence</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>DNA, Complementary</topic><topic>Enzyme Stability</topic><topic>Errors of metabolism</topic><topic>Escherichia coli - metabolism</topic><topic>Female</topic><topic>Gene Function</topic><topic>Homocysteine - metabolism</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>hyperhomocysteinemia</topic><topic>Kidney - metabolism</topic><topic>letter</topic><topic>Liver - metabolism</topic><topic>Lymphocytes - metabolism</topic><topic>Male</topic><topic>man</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Methylenetetrahydrofolate Reductase (NADPH2)</topic><topic>Middle Aged</topic><topic>Molecular Sequence Data</topic><topic>MTHFR gene</topic><topic>Mutagenesis, Site-Directed</topic><topic>Mutation</topic><topic>Oxidoreductases Acting on CH-NH Group Donors - deficiency</topic><topic>Oxidoreductases Acting on CH-NH Group Donors - genetics</topic><topic>Quebec</topic><topic>Risk Factors</topic><topic>Temperature</topic><topic>vascular disease</topic><topic>Vascular Diseases - epidemiology</topic><topic>Vascular Diseases - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Frosst, P</creatorcontrib><creatorcontrib>Blom, H.J</creatorcontrib><creatorcontrib>Milos, R</creatorcontrib><creatorcontrib>Goyette, P</creatorcontrib><creatorcontrib>Sheppard, C.A</creatorcontrib><creatorcontrib>Matthews, R.G</creatorcontrib><creatorcontrib>Boers, G.J.H</creatorcontrib><creatorcontrib>den Heijer, M</creatorcontrib><creatorcontrib>Kluijtmans, L.A.J</creatorcontrib><creatorcontrib>van den Heuve, L.P</creatorcontrib><creatorcontrib>Rozen, R</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>Human Genome Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Nature genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Frosst, P</au><au>Blom, H.J</au><au>Milos, R</au><au>Goyette, P</au><au>Sheppard, C.A</au><au>Matthews, R.G</au><au>Boers, G.J.H</au><au>den Heijer, M</au><au>Kluijtmans, L.A.J</au><au>van den Heuve, L.P</au><au>Rozen, R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>1995-05-01</date><risdate>1995</risdate><volume>10</volume><issue>1</issue><spage>111</spage><epage>113</epage><pages>111-113</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><coden>NGENEC</coden><abstract>Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease
1–4
. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism
1,5–7
. 5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetra-hydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease
5,6
. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts;
in vitro
expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>7647779</pmid><doi>10.1038/ng0595-111</doi><tpages>3</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature genetics, 1995-05, Vol.10 (1), p.111-113 |
| issn | 1061-4036 1546-1718 |
| language | eng |
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| subjects | 5,10-methylenetetrahydrofolate reductase Adult Agriculture Aminoacid disorders Animal Genetics and Genomics Base Sequence Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Research DNA, Complementary Enzyme Stability Errors of metabolism Escherichia coli - metabolism Female Gene Function Homocysteine - metabolism Human Genetics Humans hyperhomocysteinemia Kidney - metabolism letter Liver - metabolism Lymphocytes - metabolism Male man Medical sciences Metabolic diseases Methylenetetrahydrofolate Reductase (NADPH2) Middle Aged Molecular Sequence Data MTHFR gene Mutagenesis, Site-Directed Mutation Oxidoreductases Acting on CH-NH Group Donors - deficiency Oxidoreductases Acting on CH-NH Group Donors - genetics Quebec Risk Factors Temperature vascular disease Vascular Diseases - epidemiology Vascular Diseases - genetics |
| title | A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase |
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