Related Experiment Videos
A point mutation (Arg271-->Cys) of a homozygote for dysfunctional prothrombin, prothrombin Obihiro, which has a
1Laboratory of Thrombosis Research, National Cardiovascular Centre Research Institute, Suita, Japan.
Abstract:
The molecular defect of a congenitally dysfunctional form of prothrombin, prothrombin Obihiro, was identified in a patient with a severe bleeding tendency. He showed reduced fibrinogen clotting activity, despite a normal prothrombin antigen level. Nucleotide sequencing of amplified DNA revealed a C-->T change at nucleotide 7311 of exon VIII of the prothrombin gene. This resulted in the substitution of Arg271 by Cys at the factor Xa cleavage site which precludes normal activation of prothrombin Obihiro by factor Xa and the generation of thrombin. The proband was homozygous for this mutation. In addition, seven new nucleotide changes were identified in the prothrombin gene of this patient by comparison with the published gene sequence. Three polymorphisms at nucleotides 4291, 4298 and 7223 were exclusively identified in the prothrombin gene from Japanese. Particularly in the region containing exon VI and introns E and F (nucleotides 4048-4303), the prothrombin gene proved to be of high-sequence variability.
Insights
A genetic mutation in the prothrombin gene causes prothrombin Obihiro, a dysfunctional protein leading to severe bleeding disorders. This defect prevents normal thrombin generation, impacting blood clotting.
Area of Science:
- Hematology
- Molecular Genetics
- Biochemistry
Background:
- Congenital bleeding disorders often stem from defects in coagulation factors.
- Prothrombin is a critical protein in the blood coagulation cascade, essential for thrombin generation.
Observation:
- A patient presented with a severe bleeding tendency and reduced fibrinogen clotting activity, despite normal prothrombin levels.
- Genetic analysis identified a homozygous C-to-T mutation at nucleotide 7311 in exon VIII of the prothrombin gene.
Findings:
- The identified mutation results in an Arg271Cys substitution at the factor Xa cleavage site.
- This alteration prevents normal activation of prothrombin Obihiro by factor Xa, inhibiting thrombin formation.
- Seven novel nucleotide changes and three Japanese-specific polymorphisms were also noted in the prothrombin gene, highlighting sequence variability.
Implications:
- This finding elucidates the molecular basis of a dysfunctional prothrombin variant, prothrombin Obihiro.
- Understanding this defect provides insight into the structure-function relationship of prothrombin and its activation mechanism.
- The high sequence variability observed in specific gene regions may contribute to the diversity of prothrombin-related disorders.