Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its...
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| Veröffentlicht in: | Nature (London) 2001-10, Vol.413 (6855), p.488-494 |
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| creator | Levy, Gallia G. Nichols, William C. Lian, Eric C. Foroud, Tatiana McClintick, Jeanette N. McGee, Beth M. Yang, Angela Y. Siemieniak, David R. Stark, Kenneth R. Gruppo, Ralph Sarode, Ravindra Shurin, Susan B. Chandrasekaran, Visalam Stabler, Sally P. Sabio, Hernan Bouhassira, Eric E. Upshaw, Jefferson D. Ginsburg, David Tsai, Han-Mou |
| description | Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identifed interval corresponds to a segment of a much larger transcript, identifying a new member of the
ADAMTS
family of zinc metalloproteinase genes (
ADAMTS13
). Analysis of patients' genomic DNA identified 12 mutations in the
ADAMTS13
gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis. |
| doi_str_mv | 10.1038/35097008 |
| format | Article |
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ADAMTS
family of zinc metalloproteinase genes (
ADAMTS13
). Analysis of patients' genomic DNA identified 12 mutations in the
ADAMTS13
gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/35097008</identifier><identifier>PMID: 11586351</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>ADAMTS gene ; Biological and medical sciences ; Blood ; Blood vessels ; chromosome 9 ; Chromosome Mapping ; Chromosomes, Human, Pair 9 ; Circulatory system ; DNA Mutational Analysis ; Female ; Genes ; Hematologic and hematopoietic diseases ; Humanities and Social Sciences ; Humans ; Male ; Medical disorders ; Medical sciences ; Metalloendopeptidases - blood ; Metalloendopeptidases - genetics ; Metalloendopeptidases - physiology ; Molecular Sequence Data ; multidisciplinary ; Multigene Family ; Mutation ; Pedigree ; Physical Chromosome Mapping ; Platelet diseases and coagulopathies ; Purpura, Thrombotic Thrombocytopenic - congenital ; Purpura, Thrombotic Thrombocytopenic - enzymology ; Purpura, Thrombotic Thrombocytopenic - genetics ; Science ; von Willebrand Factor - metabolism</subject><ispartof>Nature (London), 2001-10, Vol.413 (6855), p.488-494</ispartof><rights>Macmillan Magazines Ltd. 2001</rights><rights>2002 INIST-CNRS</rights><rights>COPYRIGHT 2001 Nature Publishing Group</rights><rights>Copyright Macmillan Journals Ltd. Oct 4, 2001</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c637t-273c21e97033fc0fd4039668b7bed8876aae9fd9f670e068249565259e1782bf3</citedby><cites>FETCH-LOGICAL-c637t-273c21e97033fc0fd4039668b7bed8876aae9fd9f670e068249565259e1782bf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/35097008$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/35097008$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14064616$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11586351$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Levy, Gallia G.</creatorcontrib><creatorcontrib>Nichols, William C.</creatorcontrib><creatorcontrib>Lian, Eric C.</creatorcontrib><creatorcontrib>Foroud, Tatiana</creatorcontrib><creatorcontrib>McClintick, Jeanette N.</creatorcontrib><creatorcontrib>McGee, Beth M.</creatorcontrib><creatorcontrib>Yang, Angela Y.</creatorcontrib><creatorcontrib>Siemieniak, David R.</creatorcontrib><creatorcontrib>Stark, Kenneth R.</creatorcontrib><creatorcontrib>Gruppo, Ralph</creatorcontrib><creatorcontrib>Sarode, Ravindra</creatorcontrib><creatorcontrib>Shurin, Susan B.</creatorcontrib><creatorcontrib>Chandrasekaran, Visalam</creatorcontrib><creatorcontrib>Stabler, Sally P.</creatorcontrib><creatorcontrib>Sabio, Hernan</creatorcontrib><creatorcontrib>Bouhassira, Eric E.</creatorcontrib><creatorcontrib>Upshaw, Jefferson D.</creatorcontrib><creatorcontrib>Ginsburg, David</creatorcontrib><creatorcontrib>Tsai, Han-Mou</creatorcontrib><title>Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identifed interval corresponds to a segment of a much larger transcript, identifying a new member of the
ADAMTS
family of zinc metalloproteinase genes (
ADAMTS13
). Analysis of patients' genomic DNA identified 12 mutations in the
ADAMTS13
gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.</description><subject>ADAMTS gene</subject><subject>Biological and medical sciences</subject><subject>Blood</subject><subject>Blood vessels</subject><subject>chromosome 9</subject><subject>Chromosome Mapping</subject><subject>Chromosomes, Human, Pair 9</subject><subject>Circulatory system</subject><subject>DNA Mutational Analysis</subject><subject>Female</subject><subject>Genes</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Male</subject><subject>Medical disorders</subject><subject>Medical sciences</subject><subject>Metalloendopeptidases - blood</subject><subject>Metalloendopeptidases - genetics</subject><subject>Metalloendopeptidases - physiology</subject><subject>Molecular Sequence Data</subject><subject>multidisciplinary</subject><subject>Multigene Family</subject><subject>Mutation</subject><subject>Pedigree</subject><subject>Physical Chromosome Mapping</subject><subject>Platelet diseases and coagulopathies</subject><subject>Purpura, Thrombotic Thrombocytopenic - congenital</subject><subject>Purpura, Thrombotic Thrombocytopenic - enzymology</subject><subject>Purpura, Thrombotic Thrombocytopenic - genetics</subject><subject>Science</subject><subject>von Willebrand Factor - 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in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura</title><author>Levy, Gallia G. ; Nichols, William C. ; Lian, Eric C. ; Foroud, Tatiana ; McClintick, Jeanette N. ; McGee, Beth M. ; Yang, Angela Y. ; Siemieniak, David R. ; Stark, Kenneth R. ; Gruppo, Ralph ; Sarode, Ravindra ; Shurin, Susan B. ; Chandrasekaran, Visalam ; Stabler, Sally P. ; Sabio, Hernan ; Bouhassira, Eric E. ; Upshaw, Jefferson D. ; Ginsburg, David ; Tsai, Han-Mou</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c637t-273c21e97033fc0fd4039668b7bed8876aae9fd9f670e068249565259e1782bf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>ADAMTS gene</topic><topic>Biological and medical sciences</topic><topic>Blood</topic><topic>Blood vessels</topic><topic>chromosome 9</topic><topic>Chromosome Mapping</topic><topic>Chromosomes, Human, Pair 9</topic><topic>Circulatory system</topic><topic>DNA Mutational Analysis</topic><topic>Female</topic><topic>Genes</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Male</topic><topic>Medical disorders</topic><topic>Medical sciences</topic><topic>Metalloendopeptidases - blood</topic><topic>Metalloendopeptidases - genetics</topic><topic>Metalloendopeptidases - physiology</topic><topic>Molecular Sequence Data</topic><topic>multidisciplinary</topic><topic>Multigene Family</topic><topic>Mutation</topic><topic>Pedigree</topic><topic>Physical Chromosome Mapping</topic><topic>Platelet diseases and coagulopathies</topic><topic>Purpura, Thrombotic Thrombocytopenic - congenital</topic><topic>Purpura, Thrombotic Thrombocytopenic - enzymology</topic><topic>Purpura, Thrombotic Thrombocytopenic - genetics</topic><topic>Science</topic><topic>von Willebrand Factor - 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Han-Mou</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2001-10-04</date><risdate>2001</risdate><volume>413</volume><issue>6855</issue><spage>488</spage><epage>494</epage><pages>488-494</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identifed interval corresponds to a segment of a much larger transcript, identifying a new member of the
ADAMTS
family of zinc metalloproteinase genes (
ADAMTS13
). Analysis of patients' genomic DNA identified 12 mutations in the
ADAMTS13
gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>11586351</pmid><doi>10.1038/35097008</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2001-10, Vol.413 (6855), p.488-494 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_743321864 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | ADAMTS gene Biological and medical sciences Blood Blood vessels chromosome 9 Chromosome Mapping Chromosomes, Human, Pair 9 Circulatory system DNA Mutational Analysis Female Genes Hematologic and hematopoietic diseases Humanities and Social Sciences Humans Male Medical disorders Medical sciences Metalloendopeptidases - blood Metalloendopeptidases - genetics Metalloendopeptidases - physiology Molecular Sequence Data multidisciplinary Multigene Family Mutation Pedigree Physical Chromosome Mapping Platelet diseases and coagulopathies Purpura, Thrombotic Thrombocytopenic - congenital Purpura, Thrombotic Thrombocytopenic - enzymology Purpura, Thrombotic Thrombocytopenic - genetics Science von Willebrand Factor - metabolism |
| title | Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-20T10%3A37%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mutations%20in%20a%20member%20of%20the%20ADAMTS%20gene%20family%20cause%20thrombotic%20thrombocytopenic%20purpura&rft.jtitle=Nature%20(London)&rft.au=Levy,%20Gallia%20G.&rft.date=2001-10-04&rft.volume=413&rft.issue=6855&rft.spage=488&rft.epage=494&rft.pages=488-494&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/35097008&rft_dat=%3Cgale_proqu%3EA187966740%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=204478902&rft_id=info:pmid/11586351&rft_galeid=A187966740&rfr_iscdi=true |