Hereditary Protein C Deficiency: The Australian Experience

Abstract

Hereditary protein C deficiency (HPCD) is a recognized risk factor for thrombotic disease. To examine the underlying genetic defect in more detail, the protein C gene was examined in eight families from Australia. All exons and intron/exon boundaries containing the trans lated sequence of the protein C gene were amplified using the polymerase chain reaction (PCR) and sequenced di rectly. All families were identified because of a throm botic event in the proband. Six families had type I defi ciency and two had type II. Seven mutations were found in eight different families (two apparently unrelated fam ilies shared the same mutation). Five of them were point mutations leading to amino acid substitutions, most of which occurred in the serine protease domain of the ma ture protein. One mutation produced a premature stop codon, and another led to a putative splice site mutation. All of these mutations could be detected using restriction enzyme digestion or single-strand conformation polymor phism (SSCP) analysis of PCR-derived DNA. These re sults confirm the genetic heterogeneity of HPCD. Genetic diagnosis is feasible in families in whom the defect in the proband has been identified; it overcomes some of the limitations of protein-based diagnostic methods.