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[A point mutation at Arg169 (CGG-->TGG) in hereditary protein C deficiency]
E Morishita1, H Asakura, M Saito
1Department of Laboratory Sciences, School of Health Science, Kanazawa University.
Insights
This study identifies a novel mutation in protein C (PC) causing venous sinus thrombosis and pulmonary thromboembolism in a Japanese man. The identified genetic defect in protein C (PC) highlights its critical role in preventing thrombotic events.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Protein C deficiency is a known risk factor for thrombotic disorders.
- Venous sinus thrombosis and pulmonary thromboembolism are serious conditions often linked to coagulation abnormalities.
Observation:
- A 56-year-old Japanese male presented with venous sinus thrombosis and pulmonary thromboembolism.
- The patient exhibited reduced protein C (PC) activity (66%) but normal antigen levels (106%).
- The patient's mother also showed reduced PC activity and antigen levels, suggesting a hereditary component.
Findings:
- Genetic analysis revealed the patient is heterozygous for a C to T substitution at nucleotide position 6218.
- This mutation results in an arginine to tryptophan substitution at codon 169 in the protein C heavy chain.
- The same mutation was identified in the patient's mother, confirming its hereditary nature and potential link to defective protein C activation.
Implications:
- The identified mutation may be responsible for the patient's thrombotic disorder due to defective protein C activation.
- Understanding this specific genetic defect can aid in diagnosing and managing protein C deficiency and related thrombotic events.
- Warfarin treatment has so far prevented further thrombotic episodes in the patient.
Abstract:
We investigated a 56-year-old Japanese man with protein C deficiency, who was referred to our hospital because of venous sinus thrombosis and pulmonary thromboembolism. Protein C (PC) activity and the corresponding antigen level in plasma were 66% and 106% of the normal values, respectively. Both the activity and antigen levels of protein C were reduced by approximately 50% in plasma from the patient's mother. All exons and their flanking intron regions were amplified by PCR from genomic DNA. Sequencing analysis of the PCR fragments revealed that the patient was heterozygous for a C to T substitution at nucleotide position 6218, resulting in a single amino acid substitution of arginine (CGG) by tryptophan (TGG) at codon 169 of the heavy chain. We analyzed the patient, his mother, and normal controls by a Sac II digestion study of exon 7 and found that the patient and his mother had the same C to T point mutation at base 6218. This mutation could have been responsible for the defective activation of the molecule and the resulting thrombotic disorder. The patient is now being treated with warfarin, and so far no further clinical thrombotic episode has occurred.