Department of Pediatric Gastroenterology Hepatology and Nutrition, Faculty of Medicine, Karadeniz Technical University, Trabzon 61000, Turkey.
Area di Ricerca Genetica e Malattie Rare, Bambino Gesù Children Hospital, IRCCS, 00165 Rome, Italy.
Int J Mol Sci. 2020 Jul 20;21(14):5139. doi: 10.3390/ijms21145139.
Particular fibrinogen γ chain mutations occurring in the γ-module induce changes that hamper γ-γ dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen γ chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the γ chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen γ chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen γ chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (ΔΔG) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other γ-module mutations causing HHHS.
特定的纤维蛋白原 γ 链突变发生在 γ 模块中，导致 γ-γ 二聚化受阻，并引发突变纤维蛋白原的细胞内聚集，导致纤维蛋白原输出缺陷和血浆缺乏。肝脏储存会导致肝脏疾病的发展。这种情况被称为遗传性低纤维蛋白原血症伴肝储存（HHHS）。到目前为止，已经在纤维蛋白原 γ 链中检测到了七种这样的突变。我们报告了一个额外的突变，发生在一个 3.5 岁的土耳其儿童身上，因为同时存在原因不明的转氨酶升高和低血浆纤维蛋白原水平，该儿童接受了肝活检。肝活检显示纤维蛋白原在肝细胞内储存。对三个纤维蛋白原基因的分子分析显示，孩子和他的父亲在 γ 链的第 9 外显子上发生了突变（纤维蛋白原 Trabzon Thr371Ile），而母亲和哥哥则正常。纤维蛋白原 Trabzon 代表了一种新的纤维蛋白原 γ 链突变，符合 HHHS 的标准。它在一名土耳其儿童中的发生证实了 HHHS 可以在儿童早期出现，并提供了关于导致这种疾病的纤维蛋白原 γ 链突变在全球分布的相关流行病学信息。通过分析纤维蛋白原晶体结构和计算折叠自由能变化（ΔΔG）来推断变体如何影响构象和功能，我们提出了纤维蛋白原 Trabzon 和其他导致 HHHS 的 γ 模块突变引起的细胞内聚集的机制。
