A Common Missense Variant Causing Factor XI Deficiency and Increased Bleeding Tendency in Maine Coon Cats
Hereditary factor XI (FXI) deficiency is characterized as an autosomal mild to moderate coagulopathy in humans and domestic animals. Coagulation testing revealed FXI deficiency in a core family of Maine Coon cats (MCCs) in the United States. Factor XI-deficient MCCs were homozygous for a guanine to...
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| Veröffentlicht in: | Genes 2022-04, Vol.13 (5), p.792 |
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| creator | Kuder, Henrike Dickeson, S Kent Brooks, Marjory B Kehl, Alexandra Müller, Elisabeth Gailani, David Giger, Urs |
| description | Hereditary factor XI (FXI) deficiency is characterized as an autosomal mild to moderate coagulopathy in humans and domestic animals. Coagulation testing revealed FXI deficiency in a core family of Maine Coon cats (MCCs) in the United States. Factor XI-deficient MCCs were homozygous for a guanine to adenine transition resulting in a methionine substitution for the highly conserved valine-516 in the FXI catalytic domain. Immunoblots detected FXI of normal size and quantity in plasmas of MCCs homozygous for V516M. Some FXI-deficient MCCs experienced excessive post-operative/traumatic bleeding. Screening of 263 MCCs in Europe revealed a mutant allele frequency of 0.232 (23.2%). However, V516M was not found among 100 cats of other breeds. Recombinant feline FXI-M516 (fFXI-M516) expressed ~4% of the activity of wild-type fFXI-V516 in plasma clotting assays. Furthermore, fFXIa-M516 cleaved the chromogenic substrate S-2366 with ~4.3-fold lower catalytic efficacy (kcat/Km) than fFXIa-V516, supporting a conformational alteration of the protease active site. The rate of FIX activation by fFXIa-M516 was reduced >3-fold compared with fFXIa-V516. The common missense variant FXI-V516M causes a cross-reactive material positive FXI deficiency in MCCs that is associated with mild-moderate bleeding tendencies. Given the prevalence of the variant in MCCs, genotyping is recommended prior to invasive procedures or breeding. |
| doi_str_mv | 10.3390/genes13050792 |
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Coagulation testing revealed FXI deficiency in a core family of Maine Coon cats (MCCs) in the United States. Factor XI-deficient MCCs were homozygous for a guanine to adenine transition resulting in a methionine substitution for the highly conserved valine-516 in the FXI catalytic domain. Immunoblots detected FXI of normal size and quantity in plasmas of MCCs homozygous for V516M. Some FXI-deficient MCCs experienced excessive post-operative/traumatic bleeding. Screening of 263 MCCs in Europe revealed a mutant allele frequency of 0.232 (23.2%). However, V516M was not found among 100 cats of other breeds. Recombinant feline FXI-M516 (fFXI-M516) expressed ~4% of the activity of wild-type fFXI-V516 in plasma clotting assays. Furthermore, fFXIa-M516 cleaved the chromogenic substrate S-2366 with ~4.3-fold lower catalytic efficacy (kcat/Km) than fFXIa-V516, supporting a conformational alteration of the protease active site. The rate of FIX activation by fFXIa-M516 was reduced >3-fold compared with fFXIa-V516. The common missense variant FXI-V516M causes a cross-reactive material positive FXI deficiency in MCCs that is associated with mild-moderate bleeding tendencies. Given the prevalence of the variant in MCCs, genotyping is recommended prior to invasive procedures or breeding.</description><identifier>ISSN: 2073-4425</identifier><identifier>EISSN: 2073-4425</identifier><identifier>DOI: 10.3390/genes13050792</identifier><identifier>PMID: 35627175</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Amino acids ; Animals ; Binding sites ; Bleeding ; Cats ; Clotting ; Coagulation factors ; Domestic animals ; Enzymes ; Factor XI - chemistry ; Factor XI - genetics ; Factor XI deficiency ; Factor XI Deficiency - genetics ; Factor XI Deficiency - veterinary ; Gene frequency ; Genomes ; Genotyping ; Guanine ; Hemorrhage - genetics ; Homozygote ; Laboratories ; Mammals ; Methionine ; Mutation ; Mutation, Missense ; Plasma ; Polyethylene glycol ; Valine ; Veterinary medicine</subject><ispartof>Genes, 2022-04, Vol.13 (5), p.792</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-787a2b05015e99990278d80544b33372be48cfdd3d05dc898d38ae138f893dc73</citedby><cites>FETCH-LOGICAL-c415t-787a2b05015e99990278d80544b33372be48cfdd3d05dc898d38ae138f893dc73</cites><orcidid>0000-0002-4770-4107 ; 0000-0002-4138-5782 ; 0000-0002-1547-0713</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140718/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140718/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35627175$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kuder, Henrike</creatorcontrib><creatorcontrib>Dickeson, S Kent</creatorcontrib><creatorcontrib>Brooks, Marjory B</creatorcontrib><creatorcontrib>Kehl, Alexandra</creatorcontrib><creatorcontrib>Müller, Elisabeth</creatorcontrib><creatorcontrib>Gailani, David</creatorcontrib><creatorcontrib>Giger, Urs</creatorcontrib><title>A Common Missense Variant Causing Factor XI Deficiency and Increased Bleeding Tendency in Maine Coon Cats</title><title>Genes</title><addtitle>Genes (Basel)</addtitle><description>Hereditary factor XI (FXI) deficiency is characterized as an autosomal mild to moderate coagulopathy in humans and domestic animals. Coagulation testing revealed FXI deficiency in a core family of Maine Coon cats (MCCs) in the United States. Factor XI-deficient MCCs were homozygous for a guanine to adenine transition resulting in a methionine substitution for the highly conserved valine-516 in the FXI catalytic domain. Immunoblots detected FXI of normal size and quantity in plasmas of MCCs homozygous for V516M. Some FXI-deficient MCCs experienced excessive post-operative/traumatic bleeding. Screening of 263 MCCs in Europe revealed a mutant allele frequency of 0.232 (23.2%). However, V516M was not found among 100 cats of other breeds. Recombinant feline FXI-M516 (fFXI-M516) expressed ~4% of the activity of wild-type fFXI-V516 in plasma clotting assays. Furthermore, fFXIa-M516 cleaved the chromogenic substrate S-2366 with ~4.3-fold lower catalytic efficacy (kcat/Km) than fFXIa-V516, supporting a conformational alteration of the protease active site. The rate of FIX activation by fFXIa-M516 was reduced >3-fold compared with fFXIa-V516. The common missense variant FXI-V516M causes a cross-reactive material positive FXI deficiency in MCCs that is associated with mild-moderate bleeding tendencies. Given the prevalence of the variant in MCCs, genotyping is recommended prior to invasive procedures or breeding.</description><subject>Amino acids</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Bleeding</subject><subject>Cats</subject><subject>Clotting</subject><subject>Coagulation factors</subject><subject>Domestic animals</subject><subject>Enzymes</subject><subject>Factor XI - chemistry</subject><subject>Factor XI - genetics</subject><subject>Factor XI deficiency</subject><subject>Factor XI Deficiency - genetics</subject><subject>Factor XI Deficiency - veterinary</subject><subject>Gene frequency</subject><subject>Genomes</subject><subject>Genotyping</subject><subject>Guanine</subject><subject>Hemorrhage - genetics</subject><subject>Homozygote</subject><subject>Laboratories</subject><subject>Mammals</subject><subject>Methionine</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Plasma</subject><subject>Polyethylene glycol</subject><subject>Valine</subject><subject>Veterinary medicine</subject><issn>2073-4425</issn><issn>2073-4425</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkU1LHTEUhoNYqliX3UrAjZvRfEwmmY1gx68Llm60dBdykzPXyExikxnBf2-uX6hncwLn4SEvL0I_KTnkvCVHKwiQKSeCyJZtoG1GJK_qmonND-8ttJvzHSlTE0aI-I62uGiYpFJsI3-CuziOMeDfPmcIGfBfk7wJE-7MnH1Y4XNjp5jwvwU-hd5bD8E-YhMcXgSbwGRw-NcA4NbsNQT3fPdFaHyAYi_uzkz5B_rWmyHD7uveQTfnZ9fdZXX152LRnVxVtqZiqqSShi1LIiqgLUOYVE4RUddLzrlkS6iV7Z3jjghnVascVwYoV71qubOS76DjF-_9vBzBWQhTMoO-T3406VFH4_XnS_C3ehUfdEtrIqkqgoNXQYr_Z8iTHn22MAwmQJyzZo2kTDaqYQXd_4LexTmFEm9NEdqQVvBCVS-UTTHnBP37ZyjR6x71px4Lv_cxwTv91hp_Ai78mCk</recordid><startdate>20220428</startdate><enddate>20220428</enddate><creator>Kuder, Henrike</creator><creator>Dickeson, S Kent</creator><creator>Brooks, Marjory B</creator><creator>Kehl, Alexandra</creator><creator>Müller, Elisabeth</creator><creator>Gailani, David</creator><creator>Giger, Urs</creator><general>MDPI AG</general><general>MDPI</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>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4770-4107</orcidid><orcidid>https://orcid.org/0000-0002-4138-5782</orcidid><orcidid>https://orcid.org/0000-0002-1547-0713</orcidid></search><sort><creationdate>20220428</creationdate><title>A Common Missense Variant Causing Factor XI Deficiency and Increased Bleeding Tendency in Maine Coon Cats</title><author>Kuder, Henrike ; Dickeson, S Kent ; Brooks, Marjory B ; Kehl, Alexandra ; Müller, Elisabeth ; Gailani, David ; Giger, Urs</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-787a2b05015e99990278d80544b33372be48cfdd3d05dc898d38ae138f893dc73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Amino acids</topic><topic>Animals</topic><topic>Binding sites</topic><topic>Bleeding</topic><topic>Cats</topic><topic>Clotting</topic><topic>Coagulation factors</topic><topic>Domestic animals</topic><topic>Enzymes</topic><topic>Factor XI - chemistry</topic><topic>Factor XI - genetics</topic><topic>Factor XI deficiency</topic><topic>Factor XI Deficiency - genetics</topic><topic>Factor XI Deficiency - veterinary</topic><topic>Gene frequency</topic><topic>Genomes</topic><topic>Genotyping</topic><topic>Guanine</topic><topic>Hemorrhage - genetics</topic><topic>Homozygote</topic><topic>Laboratories</topic><topic>Mammals</topic><topic>Methionine</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Plasma</topic><topic>Polyethylene glycol</topic><topic>Valine</topic><topic>Veterinary medicine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kuder, Henrike</creatorcontrib><creatorcontrib>Dickeson, S Kent</creatorcontrib><creatorcontrib>Brooks, Marjory B</creatorcontrib><creatorcontrib>Kehl, Alexandra</creatorcontrib><creatorcontrib>Müller, Elisabeth</creatorcontrib><creatorcontrib>Gailani, David</creatorcontrib><creatorcontrib>Giger, Urs</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kuder, Henrike</au><au>Dickeson, S Kent</au><au>Brooks, Marjory B</au><au>Kehl, Alexandra</au><au>Müller, Elisabeth</au><au>Gailani, David</au><au>Giger, Urs</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Common Missense Variant Causing Factor XI Deficiency and Increased Bleeding Tendency in Maine Coon Cats</atitle><jtitle>Genes</jtitle><addtitle>Genes (Basel)</addtitle><date>2022-04-28</date><risdate>2022</risdate><volume>13</volume><issue>5</issue><spage>792</spage><pages>792-</pages><issn>2073-4425</issn><eissn>2073-4425</eissn><abstract>Hereditary factor XI (FXI) deficiency is characterized as an autosomal mild to moderate coagulopathy in humans and domestic animals. Coagulation testing revealed FXI deficiency in a core family of Maine Coon cats (MCCs) in the United States. Factor XI-deficient MCCs were homozygous for a guanine to adenine transition resulting in a methionine substitution for the highly conserved valine-516 in the FXI catalytic domain. Immunoblots detected FXI of normal size and quantity in plasmas of MCCs homozygous for V516M. Some FXI-deficient MCCs experienced excessive post-operative/traumatic bleeding. Screening of 263 MCCs in Europe revealed a mutant allele frequency of 0.232 (23.2%). However, V516M was not found among 100 cats of other breeds. Recombinant feline FXI-M516 (fFXI-M516) expressed ~4% of the activity of wild-type fFXI-V516 in plasma clotting assays. Furthermore, fFXIa-M516 cleaved the chromogenic substrate S-2366 with ~4.3-fold lower catalytic efficacy (kcat/Km) than fFXIa-V516, supporting a conformational alteration of the protease active site. The rate of FIX activation by fFXIa-M516 was reduced >3-fold compared with fFXIa-V516. The common missense variant FXI-V516M causes a cross-reactive material positive FXI deficiency in MCCs that is associated with mild-moderate bleeding tendencies. Given the prevalence of the variant in MCCs, genotyping is recommended prior to invasive procedures or breeding.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>35627175</pmid><doi>10.3390/genes13050792</doi><orcidid>https://orcid.org/0000-0002-4770-4107</orcidid><orcidid>https://orcid.org/0000-0002-4138-5782</orcidid><orcidid>https://orcid.org/0000-0002-1547-0713</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amino acids Animals Binding sites Bleeding Cats Clotting Coagulation factors Domestic animals Enzymes Factor XI - chemistry Factor XI - genetics Factor XI deficiency Factor XI Deficiency - genetics Factor XI Deficiency - veterinary Gene frequency Genomes Genotyping Guanine Hemorrhage - genetics Homozygote Laboratories Mammals Methionine Mutation Mutation, Missense Plasma Polyethylene glycol Valine Veterinary medicine |
| title | A Common Missense Variant Causing Factor XI Deficiency and Increased Bleeding Tendency in Maine Coon Cats |
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