Different impact of two mutations of a novel compound heterozygous protein C deficiency with late onset thrombosis

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Protein C (PC) deficiency is a heritable condition affecting coagulation.
• Mutations in the PC gene (PROC) are known causes of PC deficiency.
• Understanding genotype-phenotype correlations is crucial for managing thrombotic risk.

Purpose of the Study:

• To investigate coagulation alterations in a protein C deficiency pedigree.
• To identify and characterize the impact of specific PC gene mutations.
• To correlate PROC mutations with clinical presentation, including cerebral hemorrhagic infarction.

Main Methods:

• Pedigree analysis of a family with a proband exhibiting cerebral hemorrhagic infarction.
• Measurement of plasma levels for PC activity (PC:A), PC antigen (PC:Ag), protein S activity (PS:A), factor V:C, and factor VIII:C.
• Sequencing of nine exons of the PC gene (PROC) to identify mutations.

Main Results:

• The proband presented with significantly reduced PC:A (26%) and PC:Ag (18%).
• Two heterozygous missense mutations, F139V and D255H, were identified in the PC gene.
• Both mutations reduced PC:A and PC:Ag levels; D255H had a more pronounced effect on PC:A, PC:Ag, and factor V:C compared to F139V.

Conclusions:

• Two distinct PROC mutations, F139V and D255H, impair protein C function.
• A compound heterozygous state for these mutations can lead to synergistic PC deficiency.
• This synergistic deficiency may result in a later onset of cerebral thrombosis.