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Six different point mutations in seven Danish families with symptomatic protein C deficiency
B Lind1, M Schwartz, S Thorsen
1Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
Insights
This study identifies six novel mutations in the protein C gene linked to hereditary protein C deficiency and increased risk of venous thromboembolism in Danish families. These genetic variations lead to reduced protein C levels, impacting blood clotting.
Area of Science:
- Genetics
- Molecular Biology
- Hematology
Background:
- Protein C deficiency is a genetic disorder increasing the risk of venous thromboembolism (VTE).
- Understanding the molecular basis of protein C deficiency is crucial for risk assessment and management.
Observation:
- Six distinct point mutations in the protein C gene were identified in seven Danish families.
- All affected individuals were heterozygotes for the identified mutations.
- Mutations were located in splice sites and protein-coding regions, including the Gla-domain, EGF-domain, and serine proteinase domain.
Findings:
- Specific mutations identified include G2992-->A (splice site), C1432-->T (Arg15Trp), G3157-->C (Gly72Arg), G8559-->C (Gly282Arg), C8571-->T (Arg286Cys), and C8695-->T (Pro327Leu).
- These mutations cosegregate with protein C deficiency in affected families.
- Affected individuals show approximately 50% reduction in both protein C antigen and functional plasma levels (Type 1 deficiency).
Implications:
- The identified mutations provide new insights into the genetic causes of protein C deficiency.
- This research contributes to understanding the molecular mechanisms underlying VTE risk in protein C deficient individuals.
- Further research can explore genotype-phenotype correlations and personalized therapeutic strategies.
Abstract:
Six different point mutations of the protein C gene are described in seven Danish families with protein C deficiency associated with an increased risk of venous thromboembolism. All affected family members are heterozygotes for the mutated protein C genotype. One mutation is a G2992-->A transition at position +5 in the 5' splice site of intron D. The other five mutations affect the protein coding region. One is a C1432-->T transition in exon III converting the highly conserved Arg15 to Trp in the Gla-domain. Another mutation is a G3157-->C transversion in exon V converting the non-conserved Gly72 to Arg in the epidermal growth factor domain. The remaining three mutations are located in non-conserved amino acid positions in exon IX and affect the serine proteinase domain. The first is a G8559-->C transversion converting Gly282 to Arg. The second is a C8571-->T transition (present in two families) converting Arg286 to Cys. The third is a C8695-->T transition converting Pro327 to Leu. In each family the protein C deficiency cosegregates or probably cosegregates (one family, G8559-->C) with the mutation. All affected family members exhibit a reduction of both the antigen and the functional plasma concentration of protein C to approximately 50% of normal indicating that the mutated protein C is not present (type 1 deficiency) or only present in low amounts in plasma. Agarose gel electrophoresis followed by Western blotting shows that the Arg15-->Trp substitution is associated with a normal as well as an abnormal migrating plasma protein C band.(ABSTRACT TRUNCATED AT 250 WORDS)