GENETIC-ANALYSIS OF A LARGE KINDRED EXHIBITING TYPE-I PROTEIN-C DEFICIENCY AND ASSOCIATED THROMBOSIS

A previously described large Vermont kindred possessing a high inciden ce of venous thromboembolism with associated Type I protein C deficien cy (1) has been genetically analyzed. All nine exons of the protein C gene, including both coding and non-coding regions, have been amplifie d from blood cell genomic DNA using the Tag DNA polymerase chain react ion (PCR) and primers corresponding to flanking intronic regions, and the products directly sequenced. An initial mutation (C-->) resulting in Thr298-->Met was observed in one arm of the family exhibiting a his tory of thrombosis and protein C deficiency and was designated protein C-VERMONT IIa. However, examination of the kindred member parent (mal e) of this arm and members of other arms of the kindred demonstrated t hat the mutation entered the arm via the genetically unrelated spouse. Further analysis of the father and members of other arms of the kindr ed revealed a different mutation (C insertion: CAT-->CCAT), resulting in a frameshift beginning at amino acid #107 (His-->Pro) and truncatio n of the protein at codon #119 of the mature protein. This mutation, c alled protein C-VERMONT IIb, is associated with protein C deficiency a nd thrombosis throughout the kindred.