Amri Y, Jouini H, Becheur M, Dabboubi R, Mahjoub B, Messaoud T, Sfar M T, Casini A, de Moerloose P, Toumi N E H
Hematology Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia.
Biochemistry Laboratory, Bechir Hamza Children's Hospital, Tunis, Tunisia.
Haemophilia. 2017 Jul;23(4):e340-e347. doi: 10.1111/hae.13268. Epub 2017 Jun 8.
Congenital dysfibrinogenemia is a rare qualitative fibrinogen deficiency. Molecular defects that result in dysfibrinogenemia are usually caused by mutations which affect fibrinopeptide release, fibrin polymerization, fibrin cross-linking or fibrinolysis.
Here, we investigated the genetic basis of hypodysfibrinogenemia in two Tunisian siblings with major bleeding.
Coagulation-related tests were performed on the patients and their family members. Functional analysis was performed in plasma fibrinogen to characterize fibrin polymerization. The sequences of fibrinogen genes were amplified and analysed by sequencing.
Coagulation studies revealed a reduced functional and a borderline low antigenic fibrinogen plasma levels with prolonged thrombin and activated partial thromboplastin times. The fibrinogen is also characterized by a markedly impaired polymerization and could incorporate into fibrin fibres to a smaller extent (22%). Mutational screening disclosed a heterozygous single nucleotide deletion (G) at c.1025, resulting in a frameshift mutation (AαGly323GlufsX79) that is predicted to delete a part of the αC-domain containing some of the FXIII cross-linking sites. Both the normal and the aberrant Aα-chain (approximately 43 kDa) were detected by electrophoretic analysis in the patients.
The new dysfunctional fibrinogen, Mahdia variant, describes its impact on fibrin assembly after the loss of the αC domains which are involved in the lateral aggregation of protofibrils. The study confirms that the truncated Aα-chain could be incorporated into mature fibrinogen molecules.
先天性异常纤维蛋白原血症是一种罕见的纤维蛋白原质量缺陷。导致异常纤维蛋白原血症的分子缺陷通常由影响纤维蛋白肽释放、纤维蛋白聚合、纤维蛋白交联或纤维蛋白溶解的突变引起。
在此，我们研究了两名患有严重出血的突尼斯同胞低异常纤维蛋白原血症的遗传基础。
对患者及其家庭成员进行凝血相关检测。对血浆纤维蛋白原进行功能分析以表征纤维蛋白聚合。扩增纤维蛋白原基因序列并通过测序进行分析。
凝血研究显示功能性纤维蛋白原和抗原性纤维蛋白原血浆水平降低，凝血酶时间和活化部分凝血活酶时间延长。该纤维蛋白原的特征还在于聚合明显受损，并且在较小程度上（22%）掺入纤维蛋白纤维中。突变筛查揭示在c.1025处存在杂合单核苷酸缺失（G），导致移码突变（AαGly323GlufsX79），预计会缺失包含一些FXIII交联位点的αC结构域的一部分。通过电泳分析在患者中检测到正常和异常的Aα链（约43 kDa）。
新的功能失调纤维蛋白原，马赫迪亚型，描述了其在参与原纤维侧向聚集的αC结构域缺失后对纤维蛋白组装的影响。该研究证实截短的Aα链可以掺入成熟的纤维蛋白原分子中。
