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Defective fibrinogen polymerization associated with a novel gamma279Ala-->Asp mutation
S O Brennan1, J M Wyatt, P Ockelford
1Molecular Pathology Laboratory, Christchurch Hospital, Christchurch, New Zealand. sob@chmeds.ac.nz
British Journal of Haematology
|February 26, 2000
Summary
A novel fibrinogen gamma-chain mutation causing menorrhagia was identified. This mutation, Ala279Asp, alters fibrin polymerization and impacts blood clotting.
Area of Science:
- Hematology
- Molecular Biology
- Biochemistry
Background:
- Investigated menorrhagia in a patient with abnormal coagulation tests.
- Suspected a fibrinogen mutation due to prolonged thrombin and reptilase times.
- Observed low functional and antigenic fibrinogen concentrations.
Observation:
- SDS-PAGE revealed a doublet gamma band, suggesting heterozygosity for a gamma-chain mutation.
- Isoelectric focusing showed increased negative charge on HPLC-isolated gamma-chains.
- Mass spectrometry indicated a 20 Da increase in gamma-chain mass, implying a 40 Da increase in 50% of molecules.
Findings:
- DNA sequencing confirmed heterozygosity for an Ala279Asp substitution in the gamma-gene.
- This mutation resulted in increased negative charge and a 44 Da mass increase.
- Fibrin polymerization assays showed delayed onset and reduced rate.
Implications:
- The Ala279Asp mutation likely perturbs fibrin polymerization by affecting DD interactions.
- This molecular defect provides insight into fibrinogen dysfunction and bleeding disorders.
- Understanding mutation-specific effects on fibrin structure and function is crucial for diagnosing and managing coagulopathies.