title: Congenital hypofibrinogenemia: characterization of two missense mutations affecting fibrinogen assembly and secretion.
abstract: Congenital hypofibrinogenemia is a rare bleeding disorder characterized by abnormally low levels of fibrinogen in plasma, generally due to heterozygous mutations in one of the three fibrinogen genes (FGA, FGB, and FGG, coding for Aalpha, Bbeta, and gamma chain, respectively). Hypofibrinogenemic patients are usually asymptomatic, whereas individuals bearing similar mutations in the homozygous or compound heterozygous state develop a severe bleeding disorder: afibrinogenemia. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations affecting fibrinogen assembly or secretion, distributed throughout the 50-kb fibrinogen gene cluster. In this study, we report the mutational screening of two unrelated hypofibrinogenemic patients leading to the identification of two missense mutations, one hitherto unknown (alphaCys45Phe), and one previously described (gammaAsn345Ser). The involvement of alphaCys45Phe and gammaAsn345Ser in the pathogenesis of hypofibrinogenemia was investigated by in-vitro expression experiments. Both mutations were demonstrated to cause a severe impairment of intracellular fibrinogen processing, either by affecting half-molecule dimerization (alphaCys45Phe) or by hampering hexamer secretion (gammaAsn345Ser).
authors.affiliation: Department of Biology and Genetics for Medical Sciences, University of Milan, Via Viotti, 3/5-20133 Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Platè
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.forename: Silvia
authors.initials: S
authors.lastname: Spena
authors.forename: Marta
authors.initials: M
authors.lastname: Spreafico
authors.forename: Sharmila
authors.initials: S
authors.lastname: Fagoonee
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Tenchini
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D017354:Point Mutation; D014162:Transfection
chemical_list: D005340:Fibrinogen