Casini A, Vilar R, Beauverd Y, Aslan D, Devreese K, Mondelaers V, Alberio L, Gubert C, de Moerloose P, Neerman-Arbez M
Division of Angiology and Haemostasis, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
Department of Genetic Medicine and Development, University Medical School of Geneva, Geneva, Switzerland.
Haemophilia. 2017 Jul;23(4):583-589. doi: 10.1111/hae.13190. Epub 2017 Mar 17.
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 γ and Bβ chains. The latter mutations are of particular interest since the Bβ-chain is considered the rate-limiting chain in the hepatic production of the fibrinogen hexamer.
The aim of this study was to study the molecular pattern of four patients with congenital hypofibrinogenaemia.
Four novel fibrinogen Bβ-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.
Three patients were heterozygous for different missense mutations located in the highly conserved β 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.
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.
先天性低纤维蛋白原血症是一种纤维蛋白原定量紊乱疾病，其特征是功能性和抗原性纤维蛋白原水平成比例降低。导致纤维蛋白原定量紊乱的突变在γ链和Bβ链保守的COOH末端球状结构域中相对常见。后一种突变尤其令人关注，因为Bβ链被认为是肝脏中纤维蛋白原六聚体产生的限速链。
本研究旨在研究4例先天性低纤维蛋白原血症患者的分子模式。
在4名症状各异的女性中鉴定出4种导致先天性低纤维蛋白原血症的新型纤维蛋白原Bβ链突变。人纤维蛋白原β链前体蛋白序列（P02675）从UniProt数据库获得。使用swisspdbviewer 4.1.0对所得模型进行分析。
3例患者为位于高度保守的β结节中的不同错义突变的杂合子：c.882G>C:Arg294Ser（Arg264Ser）、c.1298G>T:Trp433Leu（Trp403Leu）和c.1329C>G:Asn443Lys（Asn413Lys）。建模分析预测主要结构修饰可能导致纤维蛋白原分泌受损。1例患者为内含子7供体剪接突变（c.1244 + 1G>A）的杂合子，导致供体位点完全缺失。
对新的致病突变进行蛋白质建模，并比较分子、生化和临床数据，继续为纤维蛋白原紊乱的发生发展过程以及最合适治疗方法的选择提供有价值的信息。
