title: Protein modelling to understand FGB mutations leading to congenital hypofibrinogenaemia.
abstract: BACKGROUND
  Congenital hypofibrinogenaemia is a quantitative fibrinogen disorder characterized by proportionally decreased levels of functional and antigenic fibrinogen. Mutations accounting for quantitative fibrinogen disorders are relatively frequent in the conserved COOH-terminal globular domains of the γ and Bβ chains. The latter mutations are of particular interest since the Bβ-chain is considered the rate-limiting chain in the hepatic production of the fibrinogen hexamer.
  
  
  OBJECTIVE
  The aim of this study was to study the molecular pattern of four patients with congenital hypofibrinogenaemia.
  
  
  METHODS
  Four novel fibrinogen Bβ-chain mutations leading to congenital hypofibrinogenaemia were identified in four women with heterogeneous symptoms. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed using swisspdbviewer 4.1.0.
  
  
  RESULTS
  Three patients were heterozygous for different missense mutations located in the highly conserved β nodule: c.882G>C:Arg294Ser (Arg264Ser), c.1298G>T:Trp433Leu (Trp403Leu) and c.1329C>G:Asn443Lys (Asn413Lys). Modelling analyses predicted major structural modifications likely to result in impaired fibrinogen secretion. One patient was heterozygous for an intron 7 donor splice mutation (c.1244 + 1G>A), leading to the complete abolishment of the donor site.
  
  
  CONCLUSIONS
  Protein modelling of new causative mutations and comparison of molecular, biochemical and clinical data continue to yield valuable information on the development and course of fibrinogen disorders as well as on the choice of the most appropriate treatments.
authors.affiliation: Division of Angiology and Haemostasis, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: A
authors.identifier: http://orcid.org/0000-0001-7910-933X
authors.initials: A
authors.lastname: Casini
authors.affiliation: Department of Genetic Medicine and Development, University Medical School of Geneva, Geneva, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Vilar
authors.affiliation: Haematology Division, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Y
authors.initials: Y
authors.lastname: Beauverd
authors.affiliation: Pediatric Hematology Unit, Faculty of Medicine, Gazi University, Ankara, Turkey.
authors.forename: D
authors.initials: D
authors.lastname: Aslan
authors.affiliation: Coagulation Laboratory, Ghent University Hospital, Ghent, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Devreese
authors.affiliation: Department of Pediatric Hemato-oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Mondelaers
authors.affiliation: Service et Laboratoire central d'Hématologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Alberio
authors.affiliation: Department of Genetic Medicine and Development, University Medical School of Geneva, Geneva, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Gubert
authors.affiliation: Division of Angiology and Haemostasis, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: de Moerloose
authors.affiliation: Department of Genetic Medicine and Development, University Medical School of Geneva, Geneva, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Neerman-Arbez
mesh_terms: D000293:Adolescent; D000328:Adult; D000347:Afibrinogenemia / Q000235:genetics*; D002648:Child; D005260:Female; D005340:Fibrinogen / Q000737:chemistry* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D017433:Protein Structure, Secondary
chemical_list: C000592498:FGB protein, human; D005340:Fibrinogen
keywords: bleeding; congenital fibrinogen disorders; hypofibrinogenaemia; mutation; thrombosis