MOLECULAR DEFECTS IN CRM-VII DEFICIENCIES - MODELING OF MISSENSE MUTATIONS IN THE CATALYTIC DOMAIN OF FVII( FACTOR)

The molecular defects causing CRM+ factor VII deficiency were investig ated in seven unrelated subjects and several members of their families . Four missense mutations located in the catalytic domain of factor VI I were found. The previously reported (304)Arg-->Gln substitution was present in the homozygous and heterozygous forms, with different polym orphic haplotypes, thus demonstrating that it is recurrent and frequen t in the Italian population. The (310)Cys-->Phe substitution was found in the homozygous form and in the compound heterozygous condition wit h the nonsense mutation (356)Trp-->stop. Two missense mutations, (298) Met-->Ile and (342)Gly-->Arg, were found in the homozygous and in the heterozygous condition respectively. Molecular heterogeneity was furth er increased by finding of the (353)Arp-->Gln polymorphism in the doub ly heterozygous condition with the 304 and 342 mutations. Plausible ex planations for loss of FVII function were found by inspecting a model of the serine protease domain of factor VIIa. Inefficient activation o f the catalytic site is predicted for (298)Met-->Ile. (342)Gly-->Arg w ould directly distort the geometry of the 'oxyanion hole' preventing f ormation of a substrate enzyme intermediate. (310)Cys-->Phe is predict ed to have an adverse effect on tissue factor interaction. These mutat ions point to important regions of the factor VII molecule.