{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:02:13Z","timestamp":1753869733854,"version":"3.41.2"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970172","81700182"],"award-info":[{"award-number":["81970172","81700182"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hemophilia B (HB), a rare bleeding disorder, shows X\u2010linked recessive inheritance and is caused by heterogeneous variants in the FIX gene (<jats:italic>F9<\/jats:italic>) encoding coagulation factor IX (FIX). This study aimed to investigate the molecular pathogenesis of a novel Met394Thr variant causing HB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used Sanger sequencing to analyze <jats:italic>F9<\/jats:italic> sequence variants in members of a Chinese family with moderate HB. Subsequently, we performed in vitro experiments on the identified novel FIX\u2010Met394Thr variant. In addition, we performed bioinformatics analysis of the novel variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a novel missense variant (c.1181T&gt;C, p.Met394Thr) in a Chinese family with moderate HB in the proband. The proband's mother and grandmother were carriers for the variant. The identified FIX\u2010Met394Thr variant did not affect the transcription of <jats:italic>F9<\/jats:italic> and the synthesis and secretion of FIX protein. The variant may, therefore, affect the physiological function of FIX protein by disrupting its spatial conformation. In addition, another variant (c.88+75A&gt;G) in intron 1 of <jats:italic>F9<\/jats:italic> was identified in the grandmother, which may also affect FIX protein function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified FIX\u2010Met394Thr as a novel causative variant of HB. Further understanding of the molecular pathogenesis underlying FIX deficiency may guide novel strategies for precision HB therapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2147","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T16:18:05Z","timestamp":1676564285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular pathogenesis of a novel <scp>Met394Thr<\/scp> variant causing hemophilia B"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6448-2297","authenticated-orcid":false,"given":"Linna","family":"Lu","sequence":"first","affiliation":[{"name":"Institute of Hematology The Second Hospital of Shanxi Medical University  Taiyuan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Hematology The Second Hospital of Shanxi Medical University  Taiyuan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wukang","family":"Shen","sequence":"additional","affiliation":[{"name":"Institute of Hematology The Second Hospital of Shanxi Medical University  Taiyuan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuai","family":"Fang","sequence":"additional","affiliation":[{"name":"Institute of Hematology The Second Hospital of Shanxi Medical University  Taiyuan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lidong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Hematology The Second Hospital of Shanxi Medical University  Taiyuan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuchen","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Hematology The Second Hospital of Shanxi Medical University  Taiyuan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linhua","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Hematology The Second Hospital of Shanxi Medical University  Taiyuan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Hematology The Second Hospital of Shanxi Medical University  Taiyuan People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365\u20102141.1999.01767.x"},{"issue":"5","key":"e_1_2_12_3_1","first-page":"635","article-title":"Molecular genotyping of the Italian cohort of patients with hemophilia B","volume":"90","author":"Belvini D.","year":"2005","journal-title":"Haematologica"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010021\u201000278\u2010x"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102016\u201009\u2010738641"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2011.04408.x"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/bf00286666"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013574"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/299178a0"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470122938.ch6"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.009"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002520"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12958"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2003.0543a.x"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.31.1.571"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1482"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102516.2012.02906.x"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.7326\/M19\u20101208"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2008.08.009"},{"key":"e_1_2_12_20_1","first-page":"395","article-title":"Role of disulfide bonds in peptide and protein conformation","volume":"5","author":"Khoo K. K.","year":"2011","journal-title":"Amino acids, peptides and proteins in organic chemistry"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.41.29087"},{"issue":"3","key":"e_1_2_12_22_1","first-page":"862","article-title":"Factor IX Denver, ASN 346\u2010\u2010>ASP mutation resulting in a dysfunctional protein with defective factor VIIIa interaction","volume":"86","author":"Lefkowitz J. B.","year":"2001","journal-title":"Thrombosis and Haemostasis"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.2147\/TACG.S288256"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1098\u20101004(1999)13:2<160::Aid\u2010humu9>3.0.Co;2\u2010c"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250127"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1653867"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2022.03.010"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12276"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147647"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209097200"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23052762"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2021.07.008"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14046"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevEukaryotGeneExpr.v9.i1.50"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1055\/a\u20101175\u20106530"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20102001\u201015398"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15397"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010017\u20101809\u20104"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365\u20102141.2000.02389.x"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0021\u20109258(18)52895\u20107"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13423"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18010048"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00335a049"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24377"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14007"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep36932"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.2147","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.2147","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.2147","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T07:47:48Z","timestamp":1692517668000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.2147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,5]]}},"alternative-id":["10.1002\/mgg3.2147"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.2147","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"type":"print","value":"2324-9269"},{"type":"electronic","value":"2324-9269"}],"subject":[],"published":{"date-parts":[[2023,2,16]]},"assertion":[{"value":"2022-10-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2147"}}