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

Abstract

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

Hereditary Hypofibrinogenemia with Hepatic Storage

“…Overall, the above-described mechanism well reconciles with the results obtained by Burcu and collaborators [ 34 ]. They used an in-silico approach based on the calculations of protein folding free energy changes (∆∆G) between each mutant fibrinogen and the wild type counterpart.…”

“…[ 33 ] All mutations involve highly conserved residues localized in the C-terminal globular region of the γ chain, the so called γ module (comprising amino acids 148–411) ( Figure 2 ). In all cases, mutations have been reported in the heterozygous state, supporting the idea that HHHS is an autosomal dominant trait and indirectly suggesting the incompatibility with life for homozygous mutations [ 34 ].…”

“…To date, only 21 index cases characterized at the molecular level, all with a diagnosis of HHHS based on immunohistochemistry and electron microscopy findings, have been described in the English literature. Table 1 lists their main clinical features [ 26 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

“…According to the custom, fibrinogen defects have been named after the city where the proband was coming from. Among the eight different mutations identified so far in FGG , seven are non-conservative missense substitutions [ 26 , 30 , 31 , 32 , 34 , 35 ], and one is a deletion of 14 nucleotides at the end of exon 8, leading to the activation of a cryptic splice site and the consequent production of an aberrant transcript that is predicted to be translated in a protein lacking five amino acids. [ 33 ] All mutations involve highly conserved residues localized in the C-terminal globular region of the γ chain, the so called γ module (comprising amino acids 148–411) ( Figure 2 ).…”

“…As for HHHS prevalence, it should be extremely rare, and only anecdotic information are available in the literature so far: (i) Aguadilla appears to be the most common mutation worldwide (with a total of 12 described index cases): (ii) FGG mutations associated with hepatic storage have been found in Turkey, Europe (Italy, France, Serbia), US, the Far East, the Caribbean, and Saudi Arabia ( Table 1 ) [ 29 , 34 ]. With these premises, we hence checked the GnomAD for worldwide frequencies of the eight HHHS-causing mutations in the FGG gene ( Table 2 ), with the hope to determine the overall prevalence rate of this particular type of hypofibrinogenemia.…”