title: Phenotype-genotype characterization of 10 families with severe a subunit factor XIII deficiency.
abstract: Factor XIII (FXIII) deficiency is a very rare severe autosomal bleeding disorder with a frequency of 1:2,000,000 in the general population and only a few patients have been genetically characterized so far. We report a phenotype-genotype characterization of 10 unrelated Iranian patients. Two FXIII (transglutaminase) activity assays showed no FXIII activity, except a conserved residual activity in patients receiving prophylactic substitution treatment. FXIII antigen concentrations measured by two immunoassays were comparable. Genotype characterization identified four novel mutations (2 missense and 2 small deletions) and two previously reported missense mutations in the FXIII A subunit gene (F13A). Molecular modeling was carried out to reveal the structural consequences of the missense mutations, that caused the replacement of an arginine residue involved in the formation of structurally important extensive hydrogen-bonded network. The replacements [c.320G>A (p.Arg77His) in the beta-sandwich, c.868C>T (p.Arg260Cys), c.869G>A (p.Arg260His) and c.1236G>T (p.Arg382Ser) in the core domain] resulted in the loss or impairment of such H-bonded network. Energy decomposition analysis demonstrated that this situation leads to the instability and perhaps to the incorrect folding of the A subunit, that would explain the development of severe FXIII deficiency.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital and University of Milan, Italy. flora.peyvandi@unimi.it
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.forename: Liliana
authors.initials: L
authors.lastname: Tagliabue
authors.forename: Marzia
authors.initials: M
authors.lastname: Menegatti
authors.forename: Mehran
authors.initials: M
authors.lastname: Karimi
authors.forename: Istvan
authors.initials: I
authors.lastname: Komáromi
authors.forename: Eva
authors.initials: E
authors.lastname: Katona
authors.forename: Laszlo
authors.initials: L
authors.lastname: Muszbek
authors.forename: Pier Mannuccio
authors.initials: PM
authors.lastname: Mannucci
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005176:Factor XIII / Q000737:chemistry / Q000235:genetics*; D005177:Factor XIII Deficiency / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype
chemical_list: C064015:factor XIII subunit A; D005176:Factor XIII