Fibrinogen is a complex protein that plays a key role in the blood clotting process. It is a hexamer composed of two copies of three distinct chains: Aα, Bβ, and γ encoded by three genes, FGA, FGB, and FGG, clustered on the long arm of chromosome 4. Congenital fibrinogen disorders (CFDs) are divided into qualitative deficiencies (dysfibrinogenemia, hypodysfibrinogenemia) in which the mutant fibrinogen molecule is present in the circulation and quantitative deficiencies (afibrinogenemia, hypofibrinogenemia) with no mutant molecule present in the bloodstream. Phenotypic manifestations are variable, patients may be asymptomatic, or suffer from bleeding or thrombosis. Causative mutations can occur in any of the three fibrinogen genes and can affect one or both alleles. Given the large number of studies reporting on novel causative mutations for CFDs since the review on the same topic published in 2016, we performed an extensive search of the literature and list here 120 additional mutations described in both quantitative and qualitative disorders. The visualization of causative single nucleotide variations placed on the coding sequences of FGA, FGB, and FGG reveals important structure function insight for several domains of the fibrinogen molecule.

Mutations Accounting for Congenital Fibrinogen Disorders: An Update.

Congenital fibrinogen disorders encompass a broad range of fibrinogen defects characterized by a wide molecular and clinical spectrum. From the first clinical description of afibrinogenemia in 1920, many major achievements have contributed to a better understanding of these complex disorders. The finding of causative mutations in all three fibrinogen genes has contributed to reveal the molecular mechanisms involved in biosynthesis of the fibrinogen molecule and to clarify the basic processes of fibrin polymerization and fibrinolysis. The compilation of abundant cases with detailed genetic, biological, and clinical features has enabled the classification of congenital fibrinogen disorders into several types and subtypes. Thus, the recent classification of congenital fibrinogen disorder is based not only on the clottable and antigenic fibrinogen levels but also on the patient's clinical phenotype and genotype. Fibrinogen supplementation is the cornerstone of bleeding management in fibrinogen disorders. Since the discovery of blood fractionation, the method of production of fibrinogen concentrate has been progressively modified to significantly improve purity and safety. Nevertheless, the availability of such products is still limited to a few countries and the optimal threshold of fibrinogen to target is still not established. In this review, we describe the major advances that have characterized 100 years of congenital fibrinogen disorders, focusing on afibrinogenemia and dysfibrinogenemia.

One Hundred Years of Congenital Fibrinogen Disorders.

The objective of this study was to explore the molecular defects in two Chinese families with hypodysfibrinogenemia. The coagulation method and immunoturbidimetric method were used to detect plasma fibrinogen activity and plasma fibrinogen antigen. The fibrinogen genes were amplified by PCR, and suspected mutations were confirmed by reverse sequencing. Bioinformatics and model analysis were used to study the conservatism and harm of the mutations. Study showed that the Fg:C and Fg:Ag of the probands of the two families were reduced, respectively, to 0.80g/L, 0.92g/L and 1.35g/L, 1.42g/L; gene analysis revealed that the proband 1 had a heterozygous missense mutation of c.688T>G (p.γPhe230Val) in exon 7 of the FGG gene; the c.2516A>C (p.AαAsn839Thr) heterozygous missense mutation in exon 6 of the FGA gene was got by the proband 2. These mutations found in this study might be related to the hypodysfibrinogenemia.

Two Novel Heterozygous Mutations (p.γPhe230Val and p.AαAsn839Thr) Cause Hereditary Hypodysfibrinogenemia in Two Chinese Independent Families

Introduction Congenital fibrinogen disorders are characterized by heterogeneous clinical manifestations with mutations in the fibrinogen gene cluster. We aimed to describe the molecular genetics and clinical manifestations of fibrinogen abnormalities and perform genotype-phenotype correlations. Materials and methods Genetic analysis of fibrinogen genes was performed by direct sequencing. The effect of the specific missense variants on fibrinogen structure and function was analyzed using PROVEAN and PolyPhen-2 algorithms and was predicted by protein modeling. Results Thirteen mutations, including five novel mutations, were identified in the three fibrinogen genes. There was poor correlation between genotypes and phenotypes. All but one of the novel mutations in subjects were predicted to be deleterious. Protein modeling predicted that multiple ienteractions with surrounding residues for novel variants were likely to result in congenital fibrinogen disorders. Conclusion This study in a relatively large cohort of Chinese patients with congenital fibrinogen disorders enabled the identification of five new fibrinogen missense mutations. In silico modeling may represent a valuable tool for understanding amino acid residues from novel variants leading to congenital fibrinogen disorders, but it should be followed by functional studies. Clinical presentation of fibrinogen disorders was variable, possibly due to genetic and environmental modifiers.

Identification and characterization of novel mutations in Chinese patients with congenital fibrinogen disorders.

Background A novel, rare OTUD3 c.863G>A (rs78466831) in humans has been reported associated with diabetes, but the prevalence and clinical characteristics of T2DM patients with rs78466831 have not been reported before. Objective To investigate the prevalence and clinical characteristics of T2DM patients with rs78466831 and provide a basis for clinical diagnosis and treatment. Methods OTUD3 gene rs78466831 SNP was detected by Sanger sequencing in all the collected specimens of laboratory-confirmed T2DM patients and healthy people. Clinical characteristics indexes inconsisting of fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG) and a body mass index (BMI), T2DM-associated chronic complications (myocardial infarction, cerebrovascular disease, retinopathy, arterial plaque, peripheral neuropathy and nephropathy) were obtained from the clinical laboratory information systems and electronic medical record system. Clinical characteristic indicators were compared between the wild-type and variant (rs78466831) patients with T2DM. Results The prevalence of rs78466831 in the T2DM patients group was significantly higher than the healthy control in our academic center. The general characteristic indicators were not significantly different between the wild-type and rs78466831 patients with T2DM, except the family history of diabetes. Clinical laboratory indicators including HbA1c, FBG, OGTT, TC, HDL-C, LDL-C and CP had no significant difference between the two groups. The therapeutic drug and target achievement rates were not significantly different between the two groups. The incidence of diabetic retinopathy in the variant group was significantly higher than the wild-type group. Conclusions The OTUD3 gene rs78466831 was associated with T2DM and may be a biological risk factor of diabetes retinopathy.

Man Yu

Papers

Identification and characterization of novel mutations in Chinese patients with congenital fibrinogen disorders.

Prevalence and clinical characteristics of T2DM patients with OTUD3 gene rs78466831 SNP at a single academic center in China