Homozygous Type I Protein C Deficiency in Two Unrelated Families Exhibiting Thrombophilia Related to Ala₁₃₆→Pro or Arg₂₈₆→His Mutations

Summary

Separate single nucleotide mutations have been identified in two unrelated homozygous type I protein C deficient individuals suffering from thrombophilia. Each mutation, initially established by direct DNA sequencing of polymerase chain reaction amplification products, results in an amino acid substitution. The first mutation (PC_Clamart) results in an Ala₁₃₆ to Pro substitution in the protein’s second epidermal growth factor-like domain. The second mutation (PC_Mtinchen) results in an Arg₂₈₆ 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 is consistent with the difference in severity of protein C deficiency and disease in the two individuals. Both mutations result in the abolition of a naturally occurring restriction endonuclease site, thereby allowing independent confirmation of the mutations and rapid and unambiguous genetic analysis of protein C deficiency in family members. In both families, the genetic analysis has proven useful in cases where an assignment of the protein C status based upon clinical laboratory measurements was either ambiguous or incorrect.

• References

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