AUTOSOMAL RECESSIVE TRANSMISSION OF HEMOPHILIA-A DUE TO A VONWILLEBRAND-FACTOR MUTATION

The differential diagnosis of the genetic bleeding disorders, hemophil ia A and von Willebrand disease, is occasionally confounded by the clo se molecular relationship of coagulation factor VIII and von Willebran d factor (vWF). This report describes the autosomal inheritance of a h emophilia A phenotype due to a mutation of vWF that results in defecti ve factor VIII binding. The proband was a female patient with low leve ls of factor VIII activity. Polymerase chain reaction (PCR) amplificat ion and DNA sequencing were employed to examine exons encoding the put ative factor VIII binding domain of vWF. The patient was found to be h omozygous for a single point mutation causing a Thr --> Met substituti on at amino acid position 28 in the mature vWF subunit. The phenotypic expression of the mutation was determined to be recessive because het erozygous family members were clinically unaffected. Recombinant vWF c ontaining the observed amino acid substitution was expressed in COS-1 cells. The mutant vWF was processed and secreted normally, and was fun ctionally equivalent to wild-type vWF in its ability to bind to platel ets. However, the mutant failed to bind factor VIII, demonstrating tha t the mutation was functionally related to the observed hemophilia phe notype. The family we describe demonstrates the recessive inheritance of a recently recognized class of genetic bleeding disorders, we call ''autosomal hemophilia.'' We conclude that vWF mutation may be an unde r recognized cause of hemophilia, especially in cases where the inheri tance pattern is not consistent with X-linked transmission.