Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression
Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study...
Gespeichert in:
| Veröffentlicht in: | Human molecular genetics 2000-02, Vol.9 (3), p.325-331 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 331 |
|---|---|
| container_issue | 3 |
| container_start_page | 325 |
| container_title | Human molecular genetics |
| container_volume | 9 |
| creator | THEUNS, J DEL-FAVERO, J DERMAUT, B VAN DUIJN, C. M BACKHOVENS, H VAN DEN BROECK, M SERNEELS, S CORSMIT, E VAN BROECKHOVEN, C CRUTS, M |
| description | Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein. |
| doi_str_mv | 10.1093/hmg/9.3.325 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_70890629</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>17483678</sourcerecordid><originalsourceid>FETCH-LOGICAL-c409t-c95a6f1d53330e0d7fcdcbeb6591077660c2066e76d6a28cd402b19c3dac12e33</originalsourceid><addsrcrecordid>eNqF0bFv1DAUBnALgehRmNiRhRAMVa7PduLEY1VBqVSJBWbLsV96Lol92EnhuvU_x6c7CcTC5Df89D09f4S8ZrBmoMT5Zro9V2uxFrx5QlasllBx6MRTsgIl60oqkCfkRc53AEzWon1OThjIpmlqWJHHKww4e0vvTfKm96Ofd9QHOm-QJrxdRjPHtNuPPgYaB7pNmDEUFyijJudovZnR0Z9-3tDk83c6xEQvxocN-gnTh0ydz2gyUhPcccuIFH_tg3IJfUmeDWbM-Or4npJvnz5-vfxc3Xy5ur68uKlsDWqurGqMHJhrhBCA4NrBOttjLxvFoG2lBMtBSmylk4Z31tXAe6ascMYyjkKckveH3G2KPxbMs558tjiOJmBcsm6hKz_F1X8ha-tOyLYr8O0_8C4uKZQjNGeMK2AdK-jsgGyKOScc9Db5yaSdZqD3_enSn1Za6NJf0W-OkUs_ofvLHgor4N0RmGzNOCQTrM9_HG8lKBC_ASDUpC8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>211290181</pqid></control><display><type>article</type><title>Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>THEUNS, J ; DEL-FAVERO, J ; DERMAUT, B ; VAN DUIJN, C. M ; BACKHOVENS, H ; VAN DEN BROECK, M ; SERNEELS, S ; CORSMIT, E ; VAN BROECKHOVEN, C ; CRUTS, M</creator><creatorcontrib>THEUNS, J ; DEL-FAVERO, J ; DERMAUT, B ; VAN DUIJN, C. M ; BACKHOVENS, H ; VAN DEN BROECK, M ; SERNEELS, S ; CORSMIT, E ; VAN BROECKHOVEN, C ; CRUTS, M</creatorcontrib><description>Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.</description><identifier>ISSN: 0964-6906</identifier><identifier>ISSN: 1460-2083</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/9.3.325</identifier><identifier>PMID: 10655540</identifier><identifier>CODEN: HNGEE5</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Aged ; Alzheimer Disease - genetics ; Animals ; Biological and medical sciences ; Cell Line ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; DNA - blood ; DNA Mutational Analysis ; Female ; Genes, Reporter ; Genetic Variation ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Medical sciences ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Middle Aged ; Molecular Sequence Data ; Neurology ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single-Stranded Conformational ; Presenilin-1 ; PSEN1 gene ; Regulatory Sequences, Nucleic Acid ; Restriction Mapping ; Risk Factors ; Transfection</subject><ispartof>Human molecular genetics, 2000-02, Vol.9 (3), p.325-331</ispartof><rights>2000 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Feb 12, 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c409t-c95a6f1d53330e0d7fcdcbeb6591077660c2066e76d6a28cd402b19c3dac12e33</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1276090$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10655540$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>THEUNS, J</creatorcontrib><creatorcontrib>DEL-FAVERO, J</creatorcontrib><creatorcontrib>DERMAUT, B</creatorcontrib><creatorcontrib>VAN DUIJN, C. M</creatorcontrib><creatorcontrib>BACKHOVENS, H</creatorcontrib><creatorcontrib>VAN DEN BROECK, M</creatorcontrib><creatorcontrib>SERNEELS, S</creatorcontrib><creatorcontrib>CORSMIT, E</creatorcontrib><creatorcontrib>VAN BROECKHOVEN, C</creatorcontrib><creatorcontrib>CRUTS, M</creatorcontrib><title>Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.</description><subject>Aged</subject><subject>Alzheimer Disease - genetics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>DNA - blood</subject><subject>DNA Mutational Analysis</subject><subject>Female</subject><subject>Genes, Reporter</subject><subject>Genetic Variation</subject><subject>Humans</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>Neurology</subject><subject>Polymerase Chain Reaction</subject><subject>Polymorphism, Restriction Fragment Length</subject><subject>Polymorphism, Single-Stranded Conformational</subject><subject>Presenilin-1</subject><subject>PSEN1 gene</subject><subject>Regulatory Sequences, Nucleic Acid</subject><subject>Restriction Mapping</subject><subject>Risk Factors</subject><subject>Transfection</subject><issn>0964-6906</issn><issn>1460-2083</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0bFv1DAUBnALgehRmNiRhRAMVa7PduLEY1VBqVSJBWbLsV96Lol92EnhuvU_x6c7CcTC5Df89D09f4S8ZrBmoMT5Zro9V2uxFrx5QlasllBx6MRTsgIl60oqkCfkRc53AEzWon1OThjIpmlqWJHHKww4e0vvTfKm96Ofd9QHOm-QJrxdRjPHtNuPPgYaB7pNmDEUFyijJudovZnR0Z9-3tDk83c6xEQvxocN-gnTh0ydz2gyUhPcccuIFH_tg3IJfUmeDWbM-Or4npJvnz5-vfxc3Xy5ur68uKlsDWqurGqMHJhrhBCA4NrBOttjLxvFoG2lBMtBSmylk4Z31tXAe6ascMYyjkKckveH3G2KPxbMs558tjiOJmBcsm6hKz_F1X8ha-tOyLYr8O0_8C4uKZQjNGeMK2AdK-jsgGyKOScc9Db5yaSdZqD3_enSn1Za6NJf0W-OkUs_ofvLHgor4N0RmGzNOCQTrM9_HG8lKBC_ASDUpC8</recordid><startdate>20000212</startdate><enddate>20000212</enddate><creator>THEUNS, J</creator><creator>DEL-FAVERO, J</creator><creator>DERMAUT, B</creator><creator>VAN DUIJN, C. M</creator><creator>BACKHOVENS, H</creator><creator>VAN DEN BROECK, M</creator><creator>SERNEELS, S</creator><creator>CORSMIT, E</creator><creator>VAN BROECKHOVEN, C</creator><creator>CRUTS, M</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</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>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20000212</creationdate><title>Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression</title><author>THEUNS, J ; DEL-FAVERO, J ; DERMAUT, B ; VAN DUIJN, C. M ; BACKHOVENS, H ; VAN DEN BROECK, M ; SERNEELS, S ; CORSMIT, E ; VAN BROECKHOVEN, C ; CRUTS, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-c95a6f1d53330e0d7fcdcbeb6591077660c2066e76d6a28cd402b19c3dac12e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Aged</topic><topic>Alzheimer Disease - genetics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>DNA - blood</topic><topic>DNA Mutational Analysis</topic><topic>Female</topic><topic>Genes, Reporter</topic><topic>Genetic Variation</topic><topic>Humans</topic><topic>In Situ Hybridization, Fluorescence</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Molecular Sequence Data</topic><topic>Neurology</topic><topic>Polymerase Chain Reaction</topic><topic>Polymorphism, Restriction Fragment Length</topic><topic>Polymorphism, Single-Stranded Conformational</topic><topic>Presenilin-1</topic><topic>PSEN1 gene</topic><topic>Regulatory Sequences, Nucleic Acid</topic><topic>Restriction Mapping</topic><topic>Risk Factors</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>THEUNS, J</creatorcontrib><creatorcontrib>DEL-FAVERO, J</creatorcontrib><creatorcontrib>DERMAUT, B</creatorcontrib><creatorcontrib>VAN DUIJN, C. M</creatorcontrib><creatorcontrib>BACKHOVENS, H</creatorcontrib><creatorcontrib>VAN DEN BROECK, M</creatorcontrib><creatorcontrib>SERNEELS, S</creatorcontrib><creatorcontrib>CORSMIT, E</creatorcontrib><creatorcontrib>VAN BROECKHOVEN, C</creatorcontrib><creatorcontrib>CRUTS, M</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>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>THEUNS, J</au><au>DEL-FAVERO, J</au><au>DERMAUT, B</au><au>VAN DUIJN, C. M</au><au>BACKHOVENS, H</au><au>VAN DEN BROECK, M</au><au>SERNEELS, S</au><au>CORSMIT, E</au><au>VAN BROECKHOVEN, C</au><au>CRUTS, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2000-02-12</date><risdate>2000</risdate><volume>9</volume><issue>3</issue><spage>325</spage><epage>331</epage><pages>325-331</pages><issn>0964-6906</issn><issn>1460-2083</issn><eissn>1460-2083</eissn><coden>HNGEE5</coden><abstract>Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>10655540</pmid><doi>10.1093/hmg/9.3.325</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0964-6906 |
| ispartof | Human molecular genetics, 2000-02, Vol.9 (3), p.325-331 |
| issn | 0964-6906 1460-2083 1460-2083 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_70890629 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Aged Alzheimer Disease - genetics Animals Biological and medical sciences Cell Line Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases DNA - blood DNA Mutational Analysis Female Genes, Reporter Genetic Variation Humans In Situ Hybridization, Fluorescence Male Medical sciences Membrane Proteins - genetics Membrane Proteins - metabolism Mice Middle Aged Molecular Sequence Data Neurology Polymerase Chain Reaction Polymorphism, Restriction Fragment Length Polymorphism, Single-Stranded Conformational Presenilin-1 PSEN1 gene Regulatory Sequences, Nucleic Acid Restriction Mapping Risk Factors Transfection |
| title | Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-16T11%3A33%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genetic%20variability%20in%20the%20regulatory%20region%20of%20presenilin%201%20associated%20with%20risk%20for%20Alzheimer's%20disease%20and%20variable%20expression&rft.jtitle=Human%20molecular%20genetics&rft.au=THEUNS,%20J&rft.date=2000-02-12&rft.volume=9&rft.issue=3&rft.spage=325&rft.epage=331&rft.pages=325-331&rft.issn=0964-6906&rft.eissn=1460-2083&rft.coden=HNGEE5&rft_id=info:doi/10.1093/hmg/9.3.325&rft_dat=%3Cproquest_cross%3E17483678%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=211290181&rft_id=info:pmid/10655540&rfr_iscdi=true |