Molecular defects in CRM+ factor VII deficiencies: modelling of missense mutations in the catalytic domain of FVII

• F. Bernardi

• D. L. Liney

• P. Patracchini

• D. Gemmati

• C. Legnani

• P. Arcieri

• M. Pinotti

• R. Redaelli

• G. Ballerini

• S. Pemberton

• A. I. Wacey

• G. Mariani

• E. G. D. Tuddenham

• G. Marchetti

抄録

Summary. The molecular defects causing CRM+ factor VII deficiency were investigated in seven unrelated subjects and several members of their families. Four missense mutations located in the catalytic domain of factor VII were found. The previously reported 304 ArgGln substitution was present in the homozygous and heterozygous forms, with different polymorphic haplotypes, thus demonstrating that it is recurrent and frequent in the Italian population. The 310 Cys Phe substitution was found in the homozygous form and in the compound heterozygous condition with the nonsense mutation 356 Trpstop. Two missense mutations, 298 MetIle and 342 GlyArg, were found in the homozygous and in the heterozygous condition respectively. Molecular heterogeneity was further increased by finding of the 353 ArgGln polymorphism in the doubly heterozygous condition with the 304 and 342 mutations. Plausible explanations for loss of FVII function were found by inspecting a model of the serine protease domain of factor VIIa. Inefficient activation of the catalytic site is predicted for 298 MetIle. 342 GlyArg would directly distort the geometry of the ‘oxyanion hole’preventing formation of a substrate enzyme intermediate. 310 Cyshe is predicted to have an adverse effect on tissue factor interaction. These mutations point to important regions of the factor VII molecule.

収録刊行物

• British Journal of Haematology

  British Journal of Haematology 86 (3), 610-618, 1994-03

  Wiley

キーワード

• Hematology

詳細情報

• CRID: 1363951794581369984
• NII論文ID: 30035650710
• NII書誌ID: AA00574570
• DOI: 10.1111/j.1365-2141.1994.tb04793.x
• ISSN: 13652141
• ISSN: 00071048
• Web Site: https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fj.1365-2141.1994.tb04793.x
• Web Site: https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.1994.tb04793.x
• データソース種別:
  • Crossref
  • CiNii Articles