{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:36:12Z","timestamp":1792643772282,"version":"4.5.0"},"reference-count":102,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T00:00:00Z","timestamp":1646179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170133, 81770140, 31900412"],"award-info":[{"award-number":["82170133, 81770140, 31900412"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL121718"],"award-info":[{"award-number":["R01 HL121718"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R21 EY028705"],"award-info":[{"award-number":["R21 EY028705"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the F9 promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX\u2019s translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment.<\/jats:p>","DOI":"10.3390\/ijms23052762","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T08:37:16Z","timestamp":1646210236000},"page":"2762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["The Molecular Basis of FIX Deficiency in Hemophilia B"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5006-2790","authenticated-orcid":false,"given":"Guomin","family":"Shen","sequence":"first","affiliation":[{"name":"Henan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang 471023, China"},{"name":"School of Basic Medical Science, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8792-1093","authenticated-orcid":false,"given":"Meng","family":"Gao","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang 471023, China"},{"name":"School of Basic Medical Science, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2517-2231","authenticated-orcid":false,"given":"Qing","family":"Cao","sequence":"additional","affiliation":[{"name":"Henan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang 471023, China"},{"name":"School of Basic Medical Science, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weikai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/hae.13376","article-title":"The spectrum of bleeding in women and girls with haemophilia B","volume":"24","author":"Staber","year":"2017","journal-title":"Haemophilia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1136\/bmj.2.4799.1378","article-title":"Christmas disease: A condition previously mistaken for haemophilia","volume":"2","author":"Biggs","year":"1952","journal-title":"Br. 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