Expression of von Willebrand factor "Normandy": an autosomal mutation that mimics hemophilia A.
von Willebrand disease Normandy (vWD Normandy) is a recently described phenotype in which a mutant von Willebrand factor (vWF) appears structurally and functionally normal except that it does not bind to blood coagulation factor VIII. This interaction is required for normal survival of factor VIII in the circulation; consequently, vWD Normandy can present as apparent hemophilia A but with autosomal recessive rather than X chromosome-linked inheritance. A vWF missense mutation, Thr28----Met, was identified in the propositus in or near the factor VIII binding site. The corresponding mutant recombinant vWF(T28M) formed normal multimers and had normal ristocetin cofactor activity. However, vWF(T28M) exhibited the same defect in factor VIII binding as natural vWF Normandy, confirming that this mutation causes the vWD Normandy phenotype. The distinction between hemophilia A and vWD Normandy is clinically important and should be considered in families affected by apparent mild hemophilia A that fail to show strict X chromosome-linked inheritance and, particularly, in potential female carriers with low factor VIII levels attributed to extreme lyonization.
Tuley
E A
EA
Howard Hughes Medical Institute, Department of Medicine, Jewish Hospital of St. Louis, Washington, University School of Medicine, MO 63110.
Gaucher
C
C
Jorieux
S
S
Worrall
N K
NK
Sadler
J E
JE
Mazurier
C
C
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D005169:Factor VIII / Q000378:metabolism; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D015345:Oligonucleotide Probes; D010641:Phenotype; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D014162:Transfection; D014841:von Willebrand Factor / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism
D015345:Oligonucleotide Probes; D011994:Recombinant Proteins; D014841:von Willebrand Factor; C069815:von Willebrand factor Normandy; D005169:Factor VIII