Molecular Pathology Laboratory, Christchurch School of Medicine University of Otago, Christchurch, New Zealand.
Liver Int. 2010 Nov;30(10):1541-7. doi: 10.1111/j.1478-3231.2010.02312.x.
Mutation in fibrinogen genes may lead to quantitative or qualitative disorders that result in bleeding, thrombosis or hepatic fibrinogen storage disease. Only three mutations in the fibrinogen γ gene have been identified that cause hepatic endoplasmic reticulum storage of mutant fibrinogen. To investigate the possibility of hepatic fibrinogen storage disease in a 4-year-old male with persistently elevated serum aminotransferases and preserved synthetic function except for a prolonged INR. After informed consent, liver and blood samples were obtained. Liver sections were examined by light microscopy, anti-fibrinogen immunolabelling and electron microscopy. Purified fibrinogen was analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and reverse phase high performance liquid chromatography; DNA sequencing was performed using a BigDye Terminator (v. 3.1) cycle sequencing kit. Four-year-old male with persistently elevated transaminases with an INR 1.5 but otherwise normal synthetic function. Fibrinogen activity and thrombin clotting time were abnormal at 0.47 g/L and 46 s respectively. Hepatic histological examination revealed portal inflammatory infiltrates with bridging fibrosis. Clumped eosinophilic material was observed in hepatocytes that was immunoreactive to fibrinogen antisera. Ultrastructural examination showed cytoplasmic inclusions arrayed in fingerprint-like patterns. DNA sequence analysis revealed heterozygosity for a novel γ314Thr →Pro mutation (fibrinogen AI duPont) in the fibrinogen γ gene. Protein analyses showed normal patterns of Aα, Bβ and γ chains suggesting that the variant γ allele was not expressed in plasma fibrinogen. We describe only the fourth mutation to be identified, γ314Thr→Pro (fibrinogen AI duPont), giving rise to hypofibrinogenaemia and hepatic fibrinogen storage disease.
纤维蛋白原基因的突变可能导致数量或质量的异常，导致出血、血栓形成或肝纤维蛋白原储存疾病。只有三种纤维蛋白原γ基因的突变被确定导致突变纤维蛋白原在内质网中的肝储存。为了研究一个 4 岁男性持续性血清转氨酶升高和除了延长的 INR 外保留合成功能的情况下是否存在肝纤维蛋白原储存疾病的可能性，在获得知情同意后，获得了肝和血样。通过光镜、抗纤维蛋白原免疫标记和电子显微镜检查肝切片。通过十二烷基硫酸钠-聚丙烯酰胺凝胶电泳和反相高效液相色谱分析纯化的纤维蛋白原；使用 BigDye Terminator（v.3.1）循环测序试剂盒进行 DNA 测序。一个 4 岁的男性，持续性转氨酶升高，INR 为 1.5，但其他合成功能正常。纤维蛋白原活性和凝血酶凝固时间分别异常，为 0.47 g/L 和 46 秒。肝组织学检查显示门脉炎症浸润伴桥接纤维化。在肝细胞中观察到成团的嗜酸性物质，对纤维蛋白原抗血清具有免疫反应性。超微结构检查显示细胞质包涵物呈指纹状排列。DNA 序列分析显示纤维蛋白原 γ 基因中存在杂合性γ314Thr→Pro 突变（纤维蛋白原 AI duPont）。蛋白分析显示 Aα、Bβ 和 γ 链的正常模式，表明变异 γ 等位基因未在血浆纤维蛋白原中表达。我们仅描述了第四个被鉴定的突变，γ314Thr→Pro（纤维蛋白原 AI duPont），导致低纤维蛋白原血症和肝纤维蛋白原储存疾病。
