Casini A, Lukowski S, Quintard V Louvain, Crutu A, Zak M, Regazzoni S, de Moerloose P, Neerman-Arbez M
Division of Angiology and Haemostasis, University Hospitals of Geneva, Switzerland.
Department of Genetic Medicine and Development, University Medical School of Geneva, Switzerland.
Thromb Res. 2014 May;133(5):868-74. doi: 10.1016/j.thromres.2014.01.022. Epub 2014 Jan 25.
Causative mutations leading to congenital quantitative fibrinogen are frequently clustered in FGA encoding the fibrinogen Aα-chain. Mutations of FGB encoding the Bβ-chain are less common and of interest since the Bβ-chain is considered the rate-limiting factor in the hepatic production of the fibrinogen hexamer.
Four novel FGB mutations were identified in two afibrinogenemic (one new-born and one 30 years old male) and hypofibrinogenemic (a 49 years old female) patient, with heterogeneous thrombotic and bleeding phenotype. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed in SwissPdbViewer 4.1 and POV-Ray 3.7.
The FGB c.895T>C p.Y299H (numbering from the initiator Met) and the FGB c.1415G>T p.G472V were predicted to be deleterious by SIFT analysis. The first replaces an uncharged aromatic amino acid side chain by a positively charged side chain modifying the balance in the distribution of hydrophobic and hydrophilic of the 10 Å neighbourhood residues. The second replaces one non-charged aliphatic side chain by another without any changes for the 10 Å surrounding region. The FGB c.352C>T p.Q118X leads to a severe premature termination codon and the FGB intron 4: IVS4-1G>C (c719-1G>C) leads to skipping of exon 5 or usage of a cryptic acceptor site located upstream or downstream of the normal site.
The continuous characterization of novel molecular defects responsible for fibrinogen deficiency combined with modelling of mutant proteins will continue to provide a better comprehension of the complexity of fibrinogen synthesis and physiology.
导致先天性纤维蛋白原定量异常的致病突变常聚集在编码纤维蛋白原Aα链的FGA基因中。编码Bβ链的FGB基因突变较少见，但因其被认为是肝脏中纤维蛋白原六聚体产生的限速因子，所以备受关注。
在两名无纤维蛋白原血症患者（一名新生儿和一名30岁男性）和一名低纤维蛋白原血症患者（一名49岁女性）中鉴定出四个新的FGB突变，这些患者具有不同的血栓形成和出血表型。人纤维蛋白原β链前体蛋白序列（P02675）从UniProt数据库获得。所得模型在SwissPdbViewer 4.1和POV-Ray 3.7中进行分析。
通过SIFT分析预测，FGB基因c.895T>C p.Y299H（从起始甲硫氨酸开始编号）和FGB基因c.1415G>T p.G472V有害。第一个突变将一个不带电荷的芳香族氨基酸侧链替换为带正电荷的侧链，改变了10 Å邻域残基的疏水和亲水分布平衡。第二个突变将一个不带电荷的脂肪族侧链替换为另一个，而10 Å周围区域没有任何变化。FGB基因c.352C>T p.Q118X导致严重的过早终止密码子，FGB基因内含子4：IVS4-1G>C（c719-1G>C）导致外显子5缺失或使用位于正常位点上游或下游的隐蔽受体位点。
对导致纤维蛋白原缺乏的新型分子缺陷的持续表征以及突变蛋白的建模将继续有助于更好地理解纤维蛋白原合成和生理学的复杂性。
