Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI–Glu555): a cross‐reactive material positive variant defective in factor IX activation
During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with
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| Veröffentlicht in: | Journal of thrombosis and haemostasis 2004-10, Vol.2 (10), p.1782-1789 |
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| container_title | Journal of thrombosis and haemostasis |
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| creator | Zivelin, A. Ogawa, T. Bulvik, S. Landau, M. Toomey, J. R. Lane, J. Seligsohn, U. Gailani, D. |
| description | During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with |
| doi_str_mv | 10.1111/j.1538-7836.2004.00882.x |
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R. ; Lane, J. ; Seligsohn, U. ; Gailani, D.</creator><creatorcontrib>Zivelin, A. ; Ogawa, T. ; Bulvik, S. ; Landau, M. ; Toomey, J. R. ; Lane, J. ; Seligsohn, U. ; Gailani, D.</creatorcontrib><description>During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N‐terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI‐Glu555 is activated normally by FXIIa and thrombin, and FXIa‐Glu555 binds activated factor IX similarly to wild type FXIa (FXIaWT). When compared with FXIaWT, FXIa‐Glu555 activates factor IX at a greatly reduced rate (∼400‐fold), and is resistant to inhibition by antithrombin. Interestingly, FXIaWT and FXIa‐Glu555 cleave the small tripeptide substrate S‐2366 with comparable kcats. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2′ site and the P2′ residues on factor IX and antithrombin. FXI‐Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.</description><identifier>ISSN: 1538-7933</identifier><identifier>ISSN: 1538-7836</identifier><identifier>EISSN: 1538-7836</identifier><identifier>DOI: 10.1111/j.1538-7836.2004.00882.x</identifier><identifier>PMID: 15456490</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Inc</publisher><subject>Antithrombin III - pharmacology ; Binding Sites ; bleeding disorder ; factor IX ; Factor IX - metabolism ; Factor XI - analysis ; Factor XI - genetics ; Factor XI - metabolism ; Factor XI Deficiency - genetics ; factor XIa ; Homozygote ; Humans ; Kinetics ; Models, Molecular ; Mutation, Missense ; Protein Binding - genetics ; Static Electricity</subject><ispartof>Journal of thrombosis and haemostasis, 2004-10, Vol.2 (10), p.1782-1789</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4162-b02fbe60c7fce167f4887198ebe0f8e7ada3b741460d69253571691a1da1a9033</citedby><cites>FETCH-LOGICAL-c4162-b02fbe60c7fce167f4887198ebe0f8e7ada3b741460d69253571691a1da1a9033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15456490$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zivelin, A.</creatorcontrib><creatorcontrib>Ogawa, T.</creatorcontrib><creatorcontrib>Bulvik, S.</creatorcontrib><creatorcontrib>Landau, M.</creatorcontrib><creatorcontrib>Toomey, J. R.</creatorcontrib><creatorcontrib>Lane, J.</creatorcontrib><creatorcontrib>Seligsohn, U.</creatorcontrib><creatorcontrib>Gailani, D.</creatorcontrib><title>Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI–Glu555): a cross‐reactive material positive variant defective in factor IX activation</title><title>Journal of thrombosis and haemostasis</title><addtitle>J Thromb Haemost</addtitle><description>During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N‐terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI‐Glu555 is activated normally by FXIIa and thrombin, and FXIa‐Glu555 binds activated factor IX similarly to wild type FXIa (FXIaWT). When compared with FXIaWT, FXIa‐Glu555 activates factor IX at a greatly reduced rate (∼400‐fold), and is resistant to inhibition by antithrombin. Interestingly, FXIaWT and FXIa‐Glu555 cleave the small tripeptide substrate S‐2366 with comparable kcats. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2′ site and the P2′ residues on factor IX and antithrombin. FXI‐Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.</description><subject>Antithrombin III - pharmacology</subject><subject>Binding Sites</subject><subject>bleeding disorder</subject><subject>factor IX</subject><subject>Factor IX - metabolism</subject><subject>Factor XI - analysis</subject><subject>Factor XI - genetics</subject><subject>Factor XI - metabolism</subject><subject>Factor XI Deficiency - genetics</subject><subject>factor XIa</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Models, Molecular</subject><subject>Mutation, Missense</subject><subject>Protein Binding - genetics</subject><subject>Static Electricity</subject><issn>1538-7933</issn><issn>1538-7836</issn><issn>1538-7836</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1O3DAQx60KVOiWV6h8quCwwY5jx6m4IMTHViv1UJC4WY4zkbzKx9ZOFnLjEZB4hL4ZT1Inu8C1vnjG8_vP2P4jhCmJaFinq4hyJuepZCKKCUkiQqSMo8dP6PC9sPcWZ4wdoC_erwihGY_JZ3RAecJFkpFD9Pc3bMABLrXpWofvF7iA0hoLjRmw0b2HAucD1vi6GjjnuGtD1OO673Rn2wYfvwtfn15CJTAnPwJuXOv969Ozg1C3G8C17sBZXeF16-10stEhb7pxIGwZ27zdY3GPJ9005CvaL3Xl4Wi3z9Dd1eXtxc18-et6cXG-nJuEiniek7jMQRCTlgaoSMtEypRmEnIgpYRUF5rlaUITQQqRxZzxlIqMalpoqjPC2Ax93_Zdu_ZPD75TtfUGqko30PZeCZExwmUSQLkFp1c6KNXa2Vq7QVGiRoPUSo1_r0Yf1GiQmgxSj0H6bTejz2soPoQ7RwJwtgUebAXDfzdWP29vQsD-AQ6MoX8</recordid><startdate>200410</startdate><enddate>200410</enddate><creator>Zivelin, A.</creator><creator>Ogawa, T.</creator><creator>Bulvik, S.</creator><creator>Landau, M.</creator><creator>Toomey, J. R.</creator><creator>Lane, J.</creator><creator>Seligsohn, U.</creator><creator>Gailani, D.</creator><general>Blackwell Science Inc</general><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>200410</creationdate><title>Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI–Glu555): a cross‐reactive material positive variant defective in factor IX activation</title><author>Zivelin, A. ; Ogawa, T. ; Bulvik, S. ; Landau, M. ; Toomey, J. R. ; Lane, J. ; Seligsohn, U. ; Gailani, D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4162-b02fbe60c7fce167f4887198ebe0f8e7ada3b741460d69253571691a1da1a9033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Antithrombin III - pharmacology</topic><topic>Binding Sites</topic><topic>bleeding disorder</topic><topic>factor IX</topic><topic>Factor IX - metabolism</topic><topic>Factor XI - analysis</topic><topic>Factor XI - genetics</topic><topic>Factor XI - metabolism</topic><topic>Factor XI Deficiency - genetics</topic><topic>factor XIa</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Models, Molecular</topic><topic>Mutation, Missense</topic><topic>Protein Binding - genetics</topic><topic>Static Electricity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zivelin, A.</creatorcontrib><creatorcontrib>Ogawa, T.</creatorcontrib><creatorcontrib>Bulvik, S.</creatorcontrib><creatorcontrib>Landau, M.</creatorcontrib><creatorcontrib>Toomey, J. R.</creatorcontrib><creatorcontrib>Lane, J.</creatorcontrib><creatorcontrib>Seligsohn, U.</creatorcontrib><creatorcontrib>Gailani, D.</creatorcontrib><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 thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zivelin, A.</au><au>Ogawa, T.</au><au>Bulvik, S.</au><au>Landau, M.</au><au>Toomey, J. R.</au><au>Lane, J.</au><au>Seligsohn, U.</au><au>Gailani, D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI–Glu555): a cross‐reactive material positive variant defective in factor IX activation</atitle><jtitle>Journal of thrombosis and haemostasis</jtitle><addtitle>J Thromb Haemost</addtitle><date>2004-10</date><risdate>2004</risdate><volume>2</volume><issue>10</issue><spage>1782</spage><epage>1789</epage><pages>1782-1789</pages><issn>1538-7933</issn><issn>1538-7836</issn><eissn>1538-7836</eissn><abstract>During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N‐terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI‐Glu555 is activated normally by FXIIa and thrombin, and FXIa‐Glu555 binds activated factor IX similarly to wild type FXIa (FXIaWT). When compared with FXIaWT, FXIa‐Glu555 activates factor IX at a greatly reduced rate (∼400‐fold), and is resistant to inhibition by antithrombin. Interestingly, FXIaWT and FXIa‐Glu555 cleave the small tripeptide substrate S‐2366 with comparable kcats. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2′ site and the P2′ residues on factor IX and antithrombin. FXI‐Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Inc</pub><pmid>15456490</pmid><doi>10.1111/j.1538-7836.2004.00882.x</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Antithrombin III - pharmacology Binding Sites bleeding disorder factor IX Factor IX - metabolism Factor XI - analysis Factor XI - genetics Factor XI - metabolism Factor XI Deficiency - genetics factor XIa Homozygote Humans Kinetics Models, Molecular Mutation, Missense Protein Binding - genetics Static Electricity |
| title | Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI–Glu555): a cross‐reactive material positive variant defective in factor IX activation |
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