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Publication Detail
Molecular characterisation and three-dimensional structural analysis of mutations in 21 unrelated families with inherited factor VII deficiency
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Peyvandi F, Jenkins PV, Mannucci PM, Billio A, Zeinali S, Perkins SJ, Perry DJ
  • Publication date:
  • Pagination:
    250, 257
  • Journal:
    Thrombosis and Haemostasis
  • Volume:
  • Issue:
  • Print ISSN:
  • Keywords:
    analysis, Blood, Blood Coagulation, database, deficiency, Epidermal Growth Factor, function, GENE, glycoprotein, growth, Mutation, plasma, secretion, Serine, Structure, Bleeding, catalytic, city, coagulation, COMPLEX, COMPLEXES, CRYSTAL, CRYSTAL STRUCTURE, crystal structures, CRYSTAL-STRUCTURES, DELETION, domain, Extraction, Factor VII, families, family, functional, GROWTH FACTOR, haemophilia, INITIATION, Iran, Italy, MED, Milan, Molecular, MUTATIONS, novel, NUMBER, Patient, patients, Protease, PROTEIN, REGION, SITE, SURFACE, Three-dimensional, Thrombosis, Tissue, tissue factor
  • Addresses:
    --- *** Royal Free & Univ Coll, Sch Med, Haemophilia Ctr, Dept Haematol, --- *** Royal Free Campus, Pond St, London NW3 2QG, England. --- *** Royal Free & Univ Coll, Sch Med, Haemophilia Ctr, Dept Haematol, London NW3 2QG, England. --- *** Royal Free & Univ Coll, Sch Med, Haemostasis Unit, Dept Haematol, London NW3 2QG, England. Angelo Bianchi Bonomi Haemophilia & Thrombosis Ct, Milan, Italy. Maggiore Hosp, IRCCS, Fdn Luigi Villa, Milan, Italy. Univ Milan, Milan, Italy. City Hosp, Dept Hematol, Bolzano, Italy. Inst Pasteur, Dept Biotechnol, Tehran, Iran. --- *** Royal Free & Univ Coll, Sch Med, Dept Biochem & Mol Biol, London, England Perry DJ --- *** Royal Free & Univ Coll, Sch Med, Haemophilia Ctr, Dept Haematol, --- *** Royal Free Campus, Pond St, London NW3 2QG, England
  • Notes:
    LA - Eng CY - GERMANY
Factor VII (FVII) is a four-domain glycoprotein that plays a critical role in the initiation of blood coagulation. Hereditary deficiencies of this plasma protein results in a bleeding diathesis that varies in severity amongst affected patients. We have analysed the FVII gene in 27 patients with FVII deficiency from 21 unrelated families predominantly of Middle-Eastern extraction. A total of 19 different mutations were identified, of which 12 were novel and 7 had been previously reported. Nine of the 12 novel mutations were missense mutations located in the Gla domain (Ser23Pro), the second epidermal growth factor domain (Cys135Arg) and the catalytic serine protease domain (Arg247Cys, Arg277Cys, Ser282Arg, Pro303Thr, Ser363Ile, Trp364Cys, Trp364Phe), of which five are homozygous. Three novel splice mutations were identified in intron 1a (IVS1a+5), intron 2 (IVS2+1) and intron 6 (IVS6+1). Of the seven previously reported mutations, five were missense mutations of which three are homozygous (Gln100Arg, Arg152Gln, Arg304Gln, Cys310Phe and Thr359Met), one was a 17 bp deletion (10585del117bp) and one was a splice site mutation within intron 7 (IVS7+7). This study has significantly extended the current database of FVII mutations, including the number of known homozygous mutations. Conformational analyses of crystal structures for FVIIa and the FVIIa-tissue factor complex provided likely explanations for the effect of the missense mutations on FVIIa secretion or function. In particular, since 23 missense mutations were located to the serine protease domain, mostly to the region between the catalytic triad and the contact surface with tissue factor, this showed that the orientation of the serine protease domain relative to bound tissue factor in the complex is crucial for functional activity
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