{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T20:08:23Z","timestamp":1770754103343,"version":"3.50.0"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2019JJ40440"],"award-info":[{"award-number":["2019JJ40440"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Hereditas"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Fibrinogen plays pivotal roles in multiple biological processes. Genetic mutation of the fibrinogen coding genes can result in congenital fibrinogen disorders (CFDs). We identified a novel heterozygous missense mutation, <jats:italic>FGG<\/jats:italic> c.1168G\u2009&gt;\u2009T (NCBI NM_000509.6), and conducted expression studies and functional analyses to explore the influence on fibrinogen synthesis, secretion, and polymerization.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Coagulation tests were performed on the patients to detect the fibrinogen concentration. Whole-exome sequencing (WES) and Sanger sequencing were employed to detect the novel mutation. Recombinant fibrinogen-producing Chinese hamster ovary (CHO) cell lines were built to examine the recombinant fibrinogen synthesis and secretion by western blotting and enzyme-linked immunosorbent assay (ELISA). The functional analysis of fibrinogen was performed by thrombin-catalyzed fibrin polymerization assay. In silico molecular analyses were carried out to elucidate the potential molecular mechanisms.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The clinical manifestations, medical history, and laboratory tests indicated the diagnosis of hypodysfibrinogenemia with bleeding phenotype in two patients. The WES and Sanger sequencing revealed that they shared the same heterozygous missense mutation, <jats:italic>FGG<\/jats:italic> c.1168G\u2009&gt;\u2009T. In the expression studies and functional analysis, the missense mutation impaired the recombinant fibrinogen's synthesis, secretion, and polymerization. Furthermore, the in silico analyses indicated novel mutation led to the hydrogen bond substitution.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The study highlighted that the novel heterozygous missense mutation, <jats:italic>FGG<\/jats:italic> c.1168G\u2009&gt;\u2009T, would change the protein secondary structure, impair the \u201cA: a\u201d interaction, and consequently deteriorate the fibrinogen synthesis, secretion, and polymerization.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s41065-024-00308-0","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T04:40:01Z","timestamp":1705552801000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A novel missense mutation (FGG c.1168G\u2009&gt;\u2009T) in the gamma chain of fibrinogen causing congenital hypodysfibrinogenemia with bleeding phenotype"],"prefix":"10.1186","volume":"161","author":[{"given":"Nuo","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhehao","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"308_CR1","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1111\/j.1538-7836.2005.01365.x","volume":"3","author":"MW Mosesson","year":"2005","unstructured":"Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost. 2005;3:1894\u2013904. https:\/\/doi.org\/10.1111\/j.1538-7836.2005.01365.x.","journal-title":"J Thromb Haemost"},{"key":"308_CR2","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1160\/th12-04-0273","volume":"108","author":"RJ Fish","year":"2012","unstructured":"Fish RJ, Neerman-Arbez M. Fibrinogen gene regulation. Thromb Haemost. 2012;108:419\u201326. https:\/\/doi.org\/10.1160\/th12-04-0273.","journal-title":"Thromb Haemost"},{"key":"308_CR3","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/s1357-2725(99)00032-1","volume":"31","author":"S Herrick","year":"1999","unstructured":"Herrick S, Blanc-Brude O, Gray A, Laurent G. Fibrinogen. Int J Biochem Cell Biol. 1999;31:741\u20136. https:\/\/doi.org\/10.1016\/s1357-2725(99)00032-1.","journal-title":"Int J Biochem Cell Biol"},{"key":"308_CR4","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1046\/j.1538-7836.2003.00063.x","volume":"1","author":"MW Mosesson","year":"2003","unstructured":"Mosesson MW. Fibrinogen gamma chain functions. J Thromb Haemost. 2003;1:231\u20138. https:\/\/doi.org\/10.1046\/j.1538-7836.2003.00063.x.","journal-title":"J Thromb Haemost"},{"key":"308_CR5","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1055\/s-0042-1756187","volume":"48","author":"A Casini","year":"2022","unstructured":"Casini A, Moerloose P, Neerman-Arbez M. One Hundred Years of Congenital Fibrinogen Disorders. Semin Thromb Hemost. 2022;48:880\u20138. https:\/\/doi.org\/10.1055\/s-0042-1756187.","journal-title":"Semin Thromb Hemost"},{"key":"308_CR6","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1111\/jth.14216","volume":"16","author":"A Casini","year":"2018","unstructured":"Casini A, Undas A, Palla R, Thachil J, de Moerloose P. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16:1887\u201390. https:\/\/doi.org\/10.1111\/jth.14216.","journal-title":"J Thromb Haemost"},{"issue":"Suppl 1","key":"308_CR7","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/j.1538-7836.2007.02465.x","volume":"5","author":"D Vu","year":"2007","unstructured":"Vu D, Neerman-Arbez M. Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins. J Thromb Haemost. 2007;5(Suppl 1):125\u201331. https:\/\/doi.org\/10.1111\/j.1538-7836.2007.02465.x.","journal-title":"J Thromb Haemost"},{"key":"308_CR8","doi-asserted-by":"publisher","first-page":"8607","DOI":"10.1021\/bi8000769","volume":"47","author":"SR Bowley","year":"2008","unstructured":"Bowley SR, Merenbloom BK, Okumura N, Betts L, Heroux A, Gorkun OV, Lord ST. Polymerization-defective fibrinogen variant gammaD364A binds knob \u201cA\u201d peptide mimic. Biochemistry. 2008;47:8607\u201313. https:\/\/doi.org\/10.1021\/bi8000769.","journal-title":"Biochemistry"},{"key":"308_CR9","doi-asserted-by":"publisher","unstructured":"T. Simurda, R. Asselta, J. Zolkova, M. Brunclikova, M. Dobrotova, Z. Kolkova, D. Loderer, I. Skornova, J. Hudecek, Z. Lasabova, J. Stasko, and P. Kubisz, Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management. Diagnostics (Basel) 11 (2021).https:\/\/doi.org\/10.3390\/diagnostics11112140","DOI":"10.3390\/diagnostics11112140"},{"key":"308_CR10","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1055\/s-0036-1571339","volume":"42","author":"A Casini","year":"2016","unstructured":"Casini A, de Moerloose P, Neerman-Arbez M. Clinical Features and Management of Congenital Fibrinogen Deficiencies. Semin Thromb Hemost. 2016;42:366\u201374. https:\/\/doi.org\/10.1055\/s-0036-1571339.","journal-title":"Semin Thromb Hemost"},{"key":"308_CR11","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1111\/jth.13655","volume":"15","author":"A Casini","year":"2017","unstructured":"Casini A, Brungs T, Lavenu-Bombled C, Vilar R, Neerman-Arbez M, de Moerloose P. Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation. J Thromb Haemost. 2017;15:876\u201388. https:\/\/doi.org\/10.1111\/jth.13655.","journal-title":"J Thromb Haemost"},{"key":"308_CR12","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1111\/ijlh.13152","volume":"42","author":"T Kaido","year":"2020","unstructured":"Kaido T, Yoda M, Kamijo T, Taira C, Higuchi Y, Okumura N. Heterozygous variant fibrinogen \u03b3A289V (Kanazawa III) was confirmed as hypodysfibrinogenemia by plasma and recombinant fibrinogens. Int J Lab Hematol. 2020;42:190\u20137. https:\/\/doi.org\/10.1111\/ijlh.13152.","journal-title":"Int J Lab Hematol"},{"key":"308_CR13","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1055\/s-0033-1349222","volume":"39","author":"P de Moerloose","year":"2013","unstructured":"de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost. 2013;39:585\u201395. https:\/\/doi.org\/10.1055\/s-0033-1349222.","journal-title":"Semin Thromb Hemost"},{"key":"308_CR14","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/275501a0","volume":"275","author":"B Blomb\u00e4ck","year":"1978","unstructured":"Blomb\u00e4ck B, Hessel B, Hogg D, Therkildsen L. A two-step fibrinogen\u2013fibrin transition in blood coagulation. Nature. 1978;275:501\u20135. https:\/\/doi.org\/10.1038\/275501a0.","journal-title":"Nature"},{"key":"308_CR15","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1021\/bi00546a028","volume":"19","author":"A.P Laudano","year":"1980","unstructured":"Laudano A.P, Doolittle R.F. Studies on synthetic peptides that bind to fibrinogen and prevent fibrin polymerization. Structural requirements, number of binding sites, and species differences. Biochemistry. 1980;19:1013\u20139. https:\/\/doi.org\/10.1021\/bi00546a028.","journal-title":"Biochemistry"},{"key":"308_CR16","doi-asserted-by":"publisher","first-page":"2888","DOI":"10.1073\/pnas.89.7.2888","volume":"89","author":"A Shimizu","year":"1992","unstructured":"Shimizu A, Nagel GM, Doolittle RF. Photoaffinity labeling of the primary fibrin polymerization site: isolation and characterization of a labeled cyanogen bromide fragment corresponding to gamma-chain residues 337\u2013379. Proc Natl Acad Sci U S A. 1992;89:2888\u201392. https:\/\/doi.org\/10.1073\/pnas.89.7.2888.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"308_CR17","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/0009-8981(77)90273-x","volume":"80","author":"J Stakenburg","year":"1977","unstructured":"Stakenburg J, Neumann H. A rapid and simple fibrinogen determination. Clin Chim Acta. 1977;80:141\u20139. https:\/\/doi.org\/10.1016\/0009-8981(77)90273-x.","journal-title":"Clin Chim Acta"},{"key":"308_CR18","doi-asserted-by":"publisher","first-page":"29596","DOI":"10.1074\/jbc.272.47.29596","volume":"272","author":"N Okumura","year":"1997","unstructured":"Okumura N, Gorkun OV, Lord ST. Severely impaired polymerization of recombinant fibrinogen gamma-364 Asp \u2013> His, the substitution discovered in a heterozygous individual. J Biol Chem. 1997;272:29596\u2013601. https:\/\/doi.org\/10.1074\/jbc.272.47.29596.","journal-title":"J Biol Chem"}],"container-title":["Hereditas"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s41065-024-00308-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s41065-024-00308-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s41065-024-00308-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T04:40:34Z","timestamp":1705552834000},"score":1,"resource":{"primary":{"URL":"https:\/\/hereditasjournal.biomedcentral.com\/articles\/10.1186\/s41065-024-00308-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,18]]},"references-count":18,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["308"],"URL":"https:\/\/doi.org\/10.1186\/s41065-024-00308-0","relation":{},"ISSN":["1601-5223"],"issn-type":[{"value":"1601-5223","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,18]]},"assertion":[{"value":"27 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was reviewed and approved by the Second Xiangya Hospital of Central South University Committee for Clinical Research, approval number NO. 2021830, and all methods were carried out under the Declaration of Helsinki. Besides, the written informed had been obtained from the patients.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4"}}