Molecular Genetics of Quantitative Fibrinogen Disorders

Abstract

Fibrinogen is a complex glycoprotein involved in the final step of the coagulation cascade as the precursor of fibrin monomers that participate in the formation of the haemostatic plug. Three genes (FGA, FGB, and FGG) clustered on chromosome 4q31.3-4q32.1 encode the three polypeptide chains (Aalpha, Bbeta, and gamma), which in a pairwise fashion form the hexameric circulating molecule. Among congenital fibrinogen deficiencies, quantitative defects (also called type I deficiencies; i.e. congenital afibrino-genemia [CAF] and hypofibrinogenemia) are characterized by the concomitant absence or reduction of coagulant activity and immunoreactive protein, while qualitative defects (type II deficiencies; i.e. dysfibrinogenemia and hypodysfibrino-genemia) show low clotting protein in contrast with normal or moderately reduced antigen. Patients affected by CAF (Mendelian Inheritance in Man, [MIM] #202400) or severe hypofibrinogenemia (MIM+134820, *134830, and *134850) may experience bleeding manifestations varying from mild to catastrophic. Although many cases of fibrinogen deficiencies have been described from a clinical point of view, only in a minority of cases the causal mutation was identified. The genetic defects so far described, most unique for any analyzed family, are invariantly located in the fibrinogen cluster; for only few of them the pathogenic role either at the protein or at the mRNA level has been investigated. This review, besides providing a concise description of the main structural and functional properties of fibrinogen and giving an overview of the clinical manifestations, the laboratory diagnosis and therapeutic approches, will be focused on the present knowledge on the genetic basis of quantitative fibrinogen deficiencies. Our systematic analysis of the available clinical and genetic data on these disorders evidences their high allelic heterogeneity, the existence of different pathogenic mechanisms, and the absence of strong genotype/phenotype correlations.

Molecular basis of quantitative fibrinogen disorders in 27 patients from India

“…Our data suggest that there may be lack of genotype–phenotype correlation among the patients with fibrinogen deficiency as observed earlier in afibrogenemia patients from Iran, Turkey and North America . For example, BL‐348 and BL‐380 were sibling pair and had inherited the c.364+1G>A mutation in FGA gene.…”

“…Such a deficiency of fibrinogen affects the formation of (fibrin‐mediated) a stable and insoluble clot. Genetic disorders involving fibrinogen have been classified as quantitative alterations (afibrinogenemia and hypofibrinogenemia), alterations of function (dysfibrinogenemia) and combined defects (hypodysfibrinogenemia) , leading to a range of bleeding or occasionally thrombotic phenotypes. More than 357 mutations resulting in hereditary deficiency of fibrinogen have been reported to date (http://www.hgmd.cf.ac.uk/ac/index.php & http://site.geht.org).…”

Lack of Association BetweenFXIII-Val34Leu,FVII-323 del/ins, and Transforming Growth Factor β1 (915G/T) Gene Polymorphisms and Bronchopulmonary Dysplasia: A Single-Center Study

“…Fibrin monomer, produced by thrombin proteolysis of fibrinogen, impairs surfactant function, and fibrin stimulates fibroblast proliferation within regions of extravascular fibrin deposition in the alveoli that is the characteristic hallmark of BPD (Acharya and Dimichele, 2008). The mutations and=or polymorphisms in the gene(s) causing abnormal polymerization, defective crosslinking, or defective assembly of the fibrinolytic system or affecting fibrinogen synthesis or processing may contribute to this process (Wilberding et al, 2001;Asselta et al, 2007;Acharya and Dimichele, 2008). Further, the evident molecular data indicate that the structure of the fibrin clot is highly dependent on FXIII activity.…”

Diagnosis, clinical features and molecular assessment of the dysfibrinogenaemias

“…Hereditary afibrinogenaemia is associated with an autosomal recessive pattern of inheritance and a range of different mutations through‐out the three fibrinogen genes. Evidence from genetic studies of quantitative disorders suggests that hypofibrinogenaemia represents heterozygosity for the same spectrum of mutations [21–23]. Quantitative fibrinogen disorders are not within the scope of this review.…”

“…Quantitative fibrinogen disorders are not within the scope of this review. However, there are a number of recent reviews available concerning the clinical expression and molecular basis of these variants [21][22][23][24][25][26][27][28].…”