Abdel Wahab Magy, de Moerloose Philippe, Fish Richard J, Neerman-Arbez Marguerite
Department of Pediatric Hematology, Cairo University Pediatric Hospital, Cairo, Egypt.
Blood Coagul Fibrinolysis. 2010 Mar;21(2):164-7. doi: 10.1097/MBC.0b013e32833678d5.
Congenital afibrinogenemia is a rare coagulation disorder attributed to over forty mutations found either in homozygosity or in compound heterozygosity, the majority localized in FGA encoding the fibrinogen Aalpha-chain. Despite the number of genetic analyses performed the study of additional patients still allows the identification of novel mutations and a better understanding of fibrinogen structure and function. Here we report the identification and functional analysis of a novel nonsense mutation in FGA exon 5: c.718C>T (CAG>TAG) p.Q240X (Q221X in the mature chain lacking the signal peptide), accounting for fibrinogen deficiency in six Egyptian patients. Expression of the mutant Aalpha-chain cDNA in combination with wild-type Bbeta-chain and gamma-chain cDNAs demonstrated that although the mutant chain could be detected in the cell media of transfected COS-7 cells it was less secreted in comparison to the wild-type Aalpha-chain. Our patients were all homozygous for p.Q240X(Q221X) yet their clinical spectrum varied considerably in their onset of presentation or severity, with bleeding ranging from moderate mucous membrane bleeds in adolescence to life threatening intracranial hemorrhage in infancy.
先天性无纤维蛋白原血症是一种罕见的凝血障碍，归因于在纯合子或复合杂合子中发现的四十多种突变，其中大多数位于编码纤维蛋白原α链的FGA中。尽管进行了大量的基因分析，但对更多患者的研究仍有助于识别新的突变，并更好地理解纤维蛋白原的结构和功能。在此，我们报告了FGA外显子5中一个新的无义突变的鉴定和功能分析：c.718C>T（CAG>TAG）p.Q240X（在缺乏信号肽的成熟链中为Q221X），该突变导致6名埃及患者出现纤维蛋白原缺乏。突变型α链cDNA与野生型β链和γ链cDNA共同表达表明，虽然在转染的COS-7细胞的细胞培养基中可以检测到突变链，但与野生型α链相比其分泌较少。我们的患者均为p.Q240X（Q221X）纯合子，但其临床表现谱在发病时间或严重程度上差异很大，出血情况从青春期的中度黏膜出血到婴儿期危及生命的颅内出血不等。
