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Three missense mutations in the protein C heavy chain causing type I and type II protein C deficiency
T Miyata1, Y Z Zheng, T Sakata
1Laboratory of Thrombosis Research, National Cardiovascular Center Research Institute, Suita, Japan.
Insights
Molecular basis of protein C deficiency was studied in three families. Specific gene mutations were identified, explaining Type I and Type II protein C deficiency in patients with thromboembolic disease.
Area of Science:
- Molecular Biology
- Genetics
- Hematology
Background:
- Protein C deficiency is linked to thromboembolic disease.
- Understanding the molecular basis is crucial for diagnosis and treatment.
Observation:
- Two patients (Osaka 1, Osaka 2) showed reduced functional and immunologic protein C levels.
- A third patient (Osaka 3) had reduced functional but normal immunologic protein C levels.
Findings:
- Protein C Osaka 1: C-to-T mutation at nt 6,218, substituting Arg-169 with Trp at the thrombin cleavage site.
- Protein C Osaka 2: G-to-A mutation at nt 8,807, substituting Met-364 with Ile in the protease domain, potentially affecting synthesis/stability.
- Protein C Osaka 3: G-to-C mutation at nt 8,868, substituting Gly-385 with Arg in the protease domain.
Implications:
- Arg-169-to-Trp and Met-364-to-Ile mutations identified as causes of Type I protein C deficiency.
- Gly-385-to-Arg mutation identified as a cause of Type II protein C deficiency.
- These findings advance the understanding of genetic thrombophilia and protein C dysfunction.
Abstract:
We have studied the molecular basis of protein C deficiency in three families with a history of thromboembolic disease. An approximately 50% reduction in both functional and immunologic levels of protein C was detected in the plasma from two unrelated patients, designated protein C Osaka 1 and protein C Osaka 2. An approximately 50% reduction in functional level but normal immunologic level of protein C was detected in plasma from a third patient, designated protein C Osaka 3. DNA sequencing of the amplified DNA revealed one missense mutation in each case. Additional mutations in the coding sequence were excluded by DNA sequencing of all protein C exons. We identified a C-to-T change at nucleotide number 6,218 of the protein C gene in protein C Osaka 1. This results in the amino acid substitution of Arg-169 by Trp at the alpha-thrombin cleavage site. In protein C Osaka 2, a G-to-A change at nucleotide number 8,807 was identified leading to the amino acid substitution of Met-364 by Ile in the protease domain. This substitution may impair the synthesis or stability of protein C Osaka 2. In protein C Osaka 3, a G-to-C change at nucleotide number 8,868 was identified. This results in substitution of Gly-385 by Arg in the protease domain. Based on these, it was concluded that Arg-169-to-Trp mutation and Met-364-to-Ile mutation cause type I protein C deficiency and Gly-385-to-Arg mutation causes type II deficiency.