title: Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency.
abstract: Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aα, Bβ, and γ, encoded by the FGA, FGB, and FGG gene, respectively). Congenital afibrinogenaemia and hypofibrinogenaemia are rare bleeding disorders characterised by abnormally low levels of functional and immunoreactive fibrinogen in plasma, associated with haemorrhagic manifestations of variable severity. While afibrinogenaemia is caused by mutations in the homozygous or compound heterozygous state in one of the three fibrinogen genes, hypofibrinogenaemia is generally due to heterozygous mutations, and is usually characterised by a milder phenotype. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations often affecting fibrinogen assembly and/or secretion. Here we report the clinical and molecular characterisation of 13 unrelated afibrinogenaemic and eight hypofibrinogenaemic patients, leading to the identification of 17 different mutations (10 hitherto unknown). All the newly-identified missense and splicing mutations werein vitro expressed to verify their pathogenic role. Our data increase the number of mutations causing quantitative fibrinogen deficiencies by about 7 %. The high number of private mutations identified in the analysed probands indicates that the full mutational screening of the three fibrinogen genes is still required for molecular diagnosis.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.forename: Manuela
authors.initials: M
authors.lastname: Platè
authors.forename: Michela
authors.initials: M
authors.lastname: Robusto
authors.forename: Munira
authors.initials: M
authors.lastname: Borhany
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guella
authors.forename: Giulia
authors.initials: G
authors.lastname: Soldà
authors.forename: Abdolreza
authors.initials: A
authors.lastname: Afrasiabi
authors.forename: Marzia
authors.initials: M
authors.lastname: Menegatti
authors.forename: Tahir
authors.initials: T
authors.lastname: Shamsi
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.affiliation: Prof. Stefano Duga, PhD, Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Viotti 3/5, 20133 Milan, Italy, Tel.: +39 02 50315823, Fax: +39 02 50315864, E-mail: stefano.duga@unimi.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D000818:Animals; D001777:Blood Coagulation / Q000235:genetics*; D001780:Blood Coagulation Tests; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005260:Female; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D014162:Transfection; D055815:Young Adult
chemical_list: D005340:Fibrinogen
keywords: Afibrinogenaemia; expression experiments; hypofibrinogenaemia; mutational screening