Structural Characteristics in the gamma Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism

Abstract

Particular fibrinogen gamma chain mutations occurring in the gamma-module induce changes that hamper gamma-gamma 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 gamma 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 gamma chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen gamma 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 gamma chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (Delta Delta G) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other gamma-module mutations causing HHHS.