title: Replacement of the Y450 (c234) phenyl ring in the carboxyl-terminal region of coagulation factor IX causes pleiotropic effects on secretion and enzyme activity.
abstract: The interplay between impaired protein biosynthesis and/or function caused by missense mutations, particularly in relation to specific protein regions, has been poorly investigated. As model we chose the severe p.Y450C mutation in the carboxyl-terminal region of coagulation factor IX (FIX) and, by expression of a panel of recombinant variants, demonstrated the key role of the tyrosine phenyl group for both FIX secretion and coagulant activity. Comparison among highly homologous coagulation serine proteases indicate that additive or compensatory pleiotropic effects on secretion and function by carboxyl-terminal mutations produce life-threatening or mild phenotypes in the presence of similarly reduced protein amounts.
authors.affiliation: Department of Life Sciences and Biotechnology and LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Branchini
authors.forename: Matteo
authors.initials: M
authors.lastname: Campioni
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Mazzucconi
authors.forename: Francesca
authors.initials: F
authors.lastname: Biondo
authors.forename: Rosella
authors.initials: R
authors.lastname: Mari
authors.forename: Maria Patrizia
authors.initials: MP
authors.lastname: Bicocchi
authors.forename: Francesco
authors.initials: F
authors.lastname: Bernardi
authors.forename: Mirko
authors.initials: M
authors.lastname: Pinotti
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D005164:Factor IX / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D005164:Factor IX
keywords: Carboxyl-terminal region; Coagulation factor IX; Dysfunctional enzyme; Gene expression; Impaired secretion; Missense mutations