title: Role of the 2 adenine (g.11293_11294insAA) insertion polymorphism in the 3' untranslated region of the factor VII (FVII) gene: molecular characterization of a patient with severe FVII deficiency.
abstract: Polymorphic variants in the gene encoding factor VII (F7) affect the plasma levels of this coagulation protein and modify the clinical phenotype of FVII deficiency in some patients. In this study we report the in vitro functional analysis of a novel polymorphic variant located in the 3' untranslated region of F7: g.11293_11294insAA. To determine whether this variant regulates FVII expression, we initially compared an expression vector containing FVII cDNA with g.11293_11294insAA with the FVII wild-type (WT) construct. The kinetics of mRNA production showed that the insertion decreases the steady-state FVII mRNA levels. To assess whether the insertion influences the phenotype of FVII-deficient patients, we evaluated its effect on the expression of FVII in a patient with severe FVII deficiency (undetectable FVII activity and antigen) carrying two additional homozygous missense variations (p.Arg277Cys and p.Arg353Gln). The two substitutions alone reduced the expression of FVII activity and antigen in vitro, but with the insertion polymorphism in our expression vector the patient's phenotype of undetectable plasma FVII was recapitulated. The insertion polymorphism in the 3' untranslated region of F7 is another modifier of FVII expression that might explain the poor genotype-phenotype correlation in some FVII-deficient patients.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Luigi Villa, IRCCS Foundation Maggiore Hospital, Mangiagalli and Regina Elena and University of Milan, Milan, Italy. flora.peyvandi@unimi.it
authors.forename: F
authors.initials: F
authors.lastname: Peyvandi
authors.forename: I
authors.initials: I
authors.lastname: Garagiola
authors.forename: R
authors.initials: R
authors.lastname: Palla
authors.forename: N
authors.initials: N
authors.lastname: Marziliano
authors.forename: P M
authors.initials: PM
authors.lastname: Mannucci
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000225:Adenine / Q000502:physiology; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D019556:COS Cells; D002522:Chlorocebus aethiops; D005167:Factor VII / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005168:Factor VII Deficiency / Q000235:genetics*; D006801:Humans; D007492:Iran / Q000208:ethnology; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020413:3' Untranslated Regions; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D005167:Factor VII; D000225:Adenine