Human coagulation factor X deficiency caused by a mutant signal peptide that blocks cleavage by signal peptidase but not targeting and translocation to the endoplasmic reticulum.

Human factor XSanto Domingo is a form of coagulation factor X in which a mutation
within the signal peptide region of the precursor protein has been correlated
genetically with a severe deficiency of factor X in the affected individual. A
point mutation results in substitution of Arg for Gly at the critical -3 position
of the factor X signal peptide. To determine the biochemical effect of this
mutation on the biosynthesis of factor X, the wild-type and mutant factor X cDNAs
were subcloned into a vector for transcription and translation in vitro.
Translation products of mRNAs encoding portions of both mutant and wild-type
proteins were used in a systematic biochemical approach to evaluate directly the
effect of the mutation on targeting, transport, and proteolytic processing in
vitro. The results show that targeting and transport of factor XSanto Domingo to
the endoplasmic reticulum are functionally dissociated from the removal of the
signal peptide by signal peptidase. Factor XSanto Domingo is translocated into
the endoplasmic reticulum but not processed by signal peptidase. Transient
expression of the wild-type and mutant factor X in human embryonic kidney 293
cells revealed apparently normal secretion of the glycosylated two-chain form of
factor X but no secretion of factor XSanto Domingo. Thus, the inability of signal
peptidase to cleave factor XSanto Domingo is directly responsible for the absence
of circulating factor X and leads to the bleeding diathesis in the affected
individual.