title: Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation.
abstract: Fibrinogen is a hexameric glycoprotein consisting of two sets of three polypeptides (the Aα, Bβ, and γ chains, encoded by the three genes FGA, FGB, and FGG). It is involved in the final phase of the coagulation process, being the precursor of the fibrin monomers necessary for the formation of the hemostatic plug. Rare inherited fibrinogen disorders can manifest as quantitative deficiencies, qualitative defects, or both. In particular, dysfibrinogenemia and hypo-dysfibrinogenemia are characterized by reduced functional activity associated with normal or reduced antigen levels, and are usually determined by heterozygous mutations affecting any of the three fibrinogen genes. In this study, we investigated the genetic basis of dys- and hypo-dysfibrinogenemia in seven unrelated patients. Mutational screening disclosed six different variants, two of which novel (FGB-p.Asp185Asn and FGG-p.Asn230Lys). The molecular characterization of the FGG-p.Asn230Lys mutation, performed by transient expression experiments of the recombinant mutant protein, demonstrated that it induces an almost complete impairment in fibrinogen secretion, according to a molecular mechanism often associated with quantitative fibrinogen disorders. Conversely, the FGB-p.Asp185Asn variant was demonstrated to be a gain-of-glycosylation mutation leading to a hyperglycosylation of the Bβ chain, not affecting fibrinogen assembly and secretion. To our knowledge, this is the second gain-of-glycosylation mutation involving the FGB gene.
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089 Rozzano Mi, Italy; Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano Mi, Italy. Electronic address: rosanna.asselta@hunimed.eu.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089 Rozzano Mi, Italy; Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano Mi, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Robusto
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom.
authors.forename: Manuela
authors.initials: M
authors.lastname: Platé
authors.affiliation: Hematology, Department of Cellular Biotechnology and Hematology, Sapienza University of Rome.
authors.forename: Cristina
authors.initials: C
authors.lastname: Santoro
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy; Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, and Luigi Villa Foundation, Milan, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089 Rozzano Mi, Italy; Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano Mi, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D005260:Female; D005340:Fibrinogen / Q000737:chemistry / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017354:Point Mutation; D016415:Sequence Alignment
chemical_list: C115499:BBeta fibrinogen; C000592498:FGB protein, human; D005340:Fibrinogen
keywords: Dysfibrinogenemia; Expression experiment; Fibrinogen; Hyperglycosylation; Hypo-dysfibrinogenemia; Mutational screening