HOMOZYGOUS TYPE-I PROTEIN-C DEFICIENCY IN 2 UNRELATED FAMILIES EXHIBITING THROMBOPHILIA RELATED TO ALA(136)-]PRO OR ARG(286)-]HIS MUTATIONS

Separate single nucleotide mutations have been identified in two unrel ated homozygous type I protein C deficient individuals suffering from thrombophilia. Each mutation, initially established by direct DNA sequ encing of polymerase chain reaction amplification products, results in an amino acid substitution. The first mutation (PCClamart) results in an Ala(136) to Pro substitution in the protein's second epidermal gro wth factor-like domain. The second mutation (PCMunchen) results in an Arg(286) to His substitution in the serine protease domain. Comparison of the location of these two mutations and the relative conservation of the two regions in homologous vitamin K-dependent plasma proteins i s consistent with the difference in severity of protein C deficiency a nd disease in the two individuals. Both mutations result in the abolit ion of a naturally occurring restriction endonuclease site, thereby al lowing independent confirmation of the mutations and rapid and unambig uous genetic analysis of protein C deficiency in family members. In bo th families, the genetic analysis has proven useful in cases where an assignment of the protein C status based upon clinical laboratory meas urements was either ambiguous or incorrect.