A novel type I factor X variant (factor X Cys350Phe) due to loss of a disulfide bond in the catalytic domain.
We report a novel mutation within the coagulation factor X (FX) that we have designated FX Padua 4. The phenotype and genotype of the proband and family members were studied. The proband was a child affected by a complex neurological syndrome who, after birth, experienced severe bleeding. The proband showed a laboratory pattern characterized by a severe reduction of FX activity and FX antigen, suggesting a true deficiency. Molecular analysis disclosed a new FX mutation localized in the catalytic domain responsible for a Cys350Phe substitution. The proband was homozygous for this mutation. The proband's mother and father showed a heterozygous pattern and had approximately one-half the normal FX activity and FX antigen. Residual purified FX Cys350Phe had an identical behavior to normal FX as showed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Molecular modeling confirms that the mutation leads to the disruption of a disulfide bridge in the catalytic region of FX. Comparison with other topologically equivalent mutations in other vitamin K-dependent proteins suggests that this disruption could adversely affect protein folding/stability, accounting for the cross-reactive material negative phenotype.
Vianello
Fabrizio
F
Department of Medical and Surgical Sciences, Second Chair of Medicine, via Ospedale 105, University of Padua Medical School, Padua, Italy. fabvian@unipd.it
Lombardi
Anna Maria
AM
Bello
Federico Dal
FD
Palù
Giorgio
G
Zanon
Ezio
E
Girolami
Antonio
A
D000328:Adult; D000941:Antigens / Q000032:analysis; D001483:Base Sequence; D020134:Catalytic Domain / Q000235:genetics; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004220:Disulfides / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005170:Factor X / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005171:Factor X Deficiency / Q000175:diagnosis / Q000235:genetics*; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype
D000941:Antigens; D004220:Disulfides; C010515:factor X antigen; D005170:Factor X