Protein modelling to understand FGB mutations leading to congenital hypofibrinogenaemia
- Author
- Alessandro Casini, R Vilar, Y Beauverd, D Aslan, Katrien Devreese (UGent) , Veerle Mondelaers (UGent) , L Alberio, C Gubert, P de Moerloose and Marguerite Neerman-Arbez
- Organization
- Abstract
- Introduction: Congenital hypofibrinogenaemia is a quantitative fibrinogen disorder characterized by proportionally decreased levels of functional and antigenic fibrinogen. Mutations accounting for quantitative fibrinogen disorders are relatively frequent in the conserved COOH-terminal globular domains of the gamma and B beta-chains. The latter mutations are of particular interest since the B beta-chain is considered the rate-limiting chain in the hepatic production of the fibrinogen hexamer. Aim: The aim of this study was to study the molecular pattern of four patients with congenital hypofibrinogenaemia. Methods: Four novel fibrinogen B beta-chain mutations leading to congenital hypofibrinogenaemia were identified in four women with heterogeneous symptoms. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed using swisspdbviewer 4.1.0. Results: Three patients were heterozygous for different missense mutations located in the highly conserved beta nodule: c.882G > C:Arg294Ser (Arg264Ser), c.1298G > T:Trp433Leu (Trp403Leu) and c.1329C > G:Asn443Lys (Asn413Lys). Modelling analyses predicted major structural modifications likely to result in impaired fibrinogen secretion. One patient was heterozygous for an intron 7 donor splice mutation (c.1244 + 1G > A), leading to the complete abolishment of the donor site. Conclusions: Protein modelling of new causative mutations and comparison of molecular, biochemical and clinical data continue to yield valuable information on the development and course of fibrinogen disorders as well as on the choice of the most appropriate treatments.
- Keywords
- bleeding, congenital fibrinogen disorders, hypofibrinogenaemia, mutation, thrombosis, INHERITED BLEEDING DISORDERS, DONOR SPLICE SITES, FIBRINOGEN DISORDERS, AFIBRINOGENEMIA, MANAGEMENT, PREGNANCY, IDENTIFICATION, DEFICIENCIES, ACTIVATION, MECHANISMS
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8504182
- MLA
- Casini, Alessandro, et al. “Protein Modelling to Understand FGB Mutations Leading to Congenital Hypofibrinogenaemia.” HAEMOPHILIA, vol. 23, no. 4, 2017, pp. 583–89, doi:10.1111/hae.13190.
- APA
- Casini, A., Vilar, R., Beauverd, Y., Aslan, D., Devreese, K., Mondelaers, V., … Neerman-Arbez, M. (2017). Protein modelling to understand FGB mutations leading to congenital hypofibrinogenaemia. HAEMOPHILIA, 23(4), 583–589. https://doi.org/10.1111/hae.13190
- Chicago author-date
- Casini, Alessandro, R Vilar, Y Beauverd, D Aslan, Katrien Devreese, Veerle Mondelaers, L Alberio, C Gubert, P de Moerloose, and Marguerite Neerman-Arbez. 2017. “Protein Modelling to Understand FGB Mutations Leading to Congenital Hypofibrinogenaemia.” HAEMOPHILIA 23 (4): 583–89. https://doi.org/10.1111/hae.13190.
- Chicago author-date (all authors)
- Casini, Alessandro, R Vilar, Y Beauverd, D Aslan, Katrien Devreese, Veerle Mondelaers, L Alberio, C Gubert, P de Moerloose, and Marguerite Neerman-Arbez. 2017. “Protein Modelling to Understand FGB Mutations Leading to Congenital Hypofibrinogenaemia.” HAEMOPHILIA 23 (4): 583–589. doi:10.1111/hae.13190.
- Vancouver
- 1.Casini A, Vilar R, Beauverd Y, Aslan D, Devreese K, Mondelaers V, et al. Protein modelling to understand FGB mutations leading to congenital hypofibrinogenaemia. HAEMOPHILIA. 2017;23(4):583–9.
- IEEE
- [1]A. Casini et al., “Protein modelling to understand FGB mutations leading to congenital hypofibrinogenaemia,” HAEMOPHILIA, vol. 23, no. 4, pp. 583–589, 2017.
@article{8504182, abstract = {{Introduction: Congenital hypofibrinogenaemia is a quantitative fibrinogen disorder characterized by proportionally decreased levels of functional and antigenic fibrinogen. Mutations accounting for quantitative fibrinogen disorders are relatively frequent in the conserved COOH-terminal globular domains of the gamma and B beta-chains. The latter mutations are of particular interest since the B beta-chain is considered the rate-limiting chain in the hepatic production of the fibrinogen hexamer. Aim: The aim of this study was to study the molecular pattern of four patients with congenital hypofibrinogenaemia. Methods: Four novel fibrinogen B beta-chain mutations leading to congenital hypofibrinogenaemia were identified in four women with heterogeneous symptoms. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed using swisspdbviewer 4.1.0. Results: Three patients were heterozygous for different missense mutations located in the highly conserved beta nodule: c.882G > C:Arg294Ser (Arg264Ser), c.1298G > T:Trp433Leu (Trp403Leu) and c.1329C > G:Asn443Lys (Asn413Lys). Modelling analyses predicted major structural modifications likely to result in impaired fibrinogen secretion. One patient was heterozygous for an intron 7 donor splice mutation (c.1244 + 1G > A), leading to the complete abolishment of the donor site. Conclusions: Protein modelling of new causative mutations and comparison of molecular, biochemical and clinical data continue to yield valuable information on the development and course of fibrinogen disorders as well as on the choice of the most appropriate treatments.}}, author = {{Casini, Alessandro and Vilar, R and Beauverd, Y and Aslan, D and Devreese, Katrien and Mondelaers, Veerle and Alberio, L and Gubert, C and de Moerloose, P and Neerman-Arbez, Marguerite}}, issn = {{1351-8216}}, journal = {{HAEMOPHILIA}}, keywords = {{bleeding,congenital fibrinogen disorders,hypofibrinogenaemia,mutation,thrombosis,INHERITED BLEEDING DISORDERS,DONOR SPLICE SITES,FIBRINOGEN DISORDERS,AFIBRINOGENEMIA,MANAGEMENT,PREGNANCY,IDENTIFICATION,DEFICIENCIES,ACTIVATION,MECHANISMS}}, language = {{eng}}, number = {{4}}, pages = {{583--589}}, title = {{Protein modelling to understand FGB mutations leading to congenital hypofibrinogenaemia}}, url = {{http://doi.org/10.1111/hae.13190}}, volume = {{23}}, year = {{2017}}, }
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