Characterization of a homozygous Gly11Val mutation in the Gla domain of coagulation factor X.
Factor (F) X deficiency is a rare inherited autosomal recessive trait. We report on a patient affected by a severe bleeding diathesis. Mutations were sought by F10 sequence analysis. The consequences of the mutation were characterized by measuring thrombin and FXa formation after triggering the clotting cascade with activated partial thromboplastin time (aPTT) reagent or with phospholipid vesicles plus either tissue factor (TF) or FIXabeta, or with the FX activator from Russell's viper venom (RVV-X). The patient was found to be homozygous for a novel FX p.G51V mutation (G11V of the mature protein) within the omega-loop of the gamma-carboxyglutamic-rich domain. FX activity was markedly reduced (FX:C <1%) in prothrombin time and aPTT assays, and was 15% of normal in the RVV-X assay. The antigen level (FX:Ag) was 75%. TF, alone or in combination with recombinant FVIIa, failed to trigger detectable FXa or thrombin activity in the patient's plasma. FIXabeta also failed to trigger measurable FXa or thrombin production, but activation with RVV-X was only 4-fold less effective in the patient's plasma than in normal plasma. Supplementation with normal FX suggested that FX(G11V) and/or FXa(G11V) might slow the clotting cascade by competition. Overall, the patient's phenotype appears to be due to a very low rate of FX(G11V) activation by TF/FVIIa and FVIIIa/FIXa complexes rather than to FXa(G11V) activity within prothrombinase.
Chafa
Ouerdia
O
INSERM U765, Paris, France.
Tagzirt
Madjid
M
Tapon-Bretaudière
Jacqueline
J
Reghis
Abderrezak
A
Fischer
Anne-Marie
AM
LeBonniec
Bernard F
BF
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D003241:Consanguinity; D005170:Factor X / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005171:Factor X Deficiency / Q000235:genetics*; D015951:Factor Xa / Q000096:biosynthesis; D005260:Female; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013917:Thrombin / Q000096:biosynthesis; D014633:Valine / Q000378:metabolism*
D011994:Recombinant Proteins; D005170:Factor X; D013917:Thrombin; D015951:Factor Xa; D014633:Valine