Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B
Abstract Background Hemophilia B (HB), a rare bleeding disorder, shows X‐linked recessive inheritance and is caused by heterogeneous variants in the FIX gene (F9) encoding coagulation factor IX (FIX). This study aimed to investigate the molecular pathogenesis of a novel Met394Thr variant causing HB....
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-05-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.2147 |
| _version_ | 1797828572014968832 |
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| author | Linna Lu Lingyu Wang Wukang Shen Shuai Fang Lidong Zhao Xuchen Hu Linhua Yang Gang Wang |
| author_facet | Linna Lu Lingyu Wang Wukang Shen Shuai Fang Lidong Zhao Xuchen Hu Linhua Yang Gang Wang |
| author_sort | Linna Lu |
| collection | DOAJ |
| description | Abstract Background Hemophilia B (HB), a rare bleeding disorder, shows X‐linked recessive inheritance and is caused by heterogeneous variants in the FIX gene (F9) encoding coagulation factor IX (FIX). This study aimed to investigate the molecular pathogenesis of a novel Met394Thr variant causing HB. Methods We used Sanger sequencing to analyze F9 sequence variants in members of a Chinese family with moderate HB. Subsequently, we performed in vitro experiments on the identified novel FIX‐Met394Thr variant. In addition, we performed bioinformatics analysis of the novel variant. Results We identified a novel missense variant (c.1181T>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‐Met394Thr variant did not affect the transcription of F9 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>G) in intron 1 of F9 was identified in the grandmother, which may also affect FIX protein function. Conclusion We identified FIX‐Met394Thr as a novel causative variant of HB. Further understanding of the molecular pathogenesis underlying FIX deficiency may guide novel strategies for precision HB therapy. |
| first_indexed | 2024-04-09T13:06:28Z |
| format | Article |
| id | doaj.art-03ef4656e4e4417eb81fc58e6c95abbb |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-04-09T13:06:28Z |
| publishDate | 2023-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-03ef4656e4e4417eb81fc58e6c95abbb2023-05-12T14:52:44ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-05-01115n/an/a10.1002/mgg3.2147Molecular pathogenesis of a novel Met394Thr variant causing hemophilia BLinna Lu0Lingyu Wang1Wukang Shen2Shuai Fang3Lidong Zhao4Xuchen Hu5Linhua Yang6Gang Wang7Institute of Hematology The Second Hospital of Shanxi Medical University Taiyuan People's Republic of ChinaInstitute of Hematology The Second Hospital of Shanxi Medical University Taiyuan People's Republic of ChinaInstitute of Hematology The Second Hospital of Shanxi Medical University Taiyuan People's Republic of ChinaInstitute of Hematology The Second Hospital of Shanxi Medical University Taiyuan People's Republic of ChinaInstitute of Hematology The Second Hospital of Shanxi Medical University Taiyuan People's Republic of ChinaInstitute of Hematology The Second Hospital of Shanxi Medical University Taiyuan People's Republic of ChinaInstitute of Hematology The Second Hospital of Shanxi Medical University Taiyuan People's Republic of ChinaInstitute of Hematology The Second Hospital of Shanxi Medical University Taiyuan People's Republic of ChinaAbstract Background Hemophilia B (HB), a rare bleeding disorder, shows X‐linked recessive inheritance and is caused by heterogeneous variants in the FIX gene (F9) encoding coagulation factor IX (FIX). This study aimed to investigate the molecular pathogenesis of a novel Met394Thr variant causing HB. Methods We used Sanger sequencing to analyze F9 sequence variants in members of a Chinese family with moderate HB. Subsequently, we performed in vitro experiments on the identified novel FIX‐Met394Thr variant. In addition, we performed bioinformatics analysis of the novel variant. Results We identified a novel missense variant (c.1181T>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‐Met394Thr variant did not affect the transcription of F9 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>G) in intron 1 of F9 was identified in the grandmother, which may also affect FIX protein function. Conclusion We identified FIX‐Met394Thr as a novel causative variant of HB. Further understanding of the molecular pathogenesis underlying FIX deficiency may guide novel strategies for precision HB therapy.https://doi.org/10.1002/mgg3.2147bioinformaticsfactor IX (FIX)hemophilia Bmolecular pathogenesisnovel variant |
| spellingShingle | Linna Lu Lingyu Wang Wukang Shen Shuai Fang Lidong Zhao Xuchen Hu Linhua Yang Gang Wang Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B Molecular Genetics & Genomic Medicine bioinformatics factor IX (FIX) hemophilia B molecular pathogenesis novel variant |
| title | Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B |
| title_full | Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B |
| title_fullStr | Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B |
| title_full_unstemmed | Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B |
| title_short | Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B |
| title_sort | molecular pathogenesis of a novel met394thr variant causing hemophilia b |
| topic | bioinformatics factor IX (FIX) hemophilia B molecular pathogenesis novel variant |
| url | https://doi.org/10.1002/mgg3.2147 |
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