COMPOUND HETEROZYGOUS PROTEIN-C DEFICIENCY RESULTING IN THE PRESENCE OF ONLY THE BETA-FORM OF PROTEIN-C IN PLASMA

About 30% of human plasma protein C (PC) is of lower molecular weight than the predominant alpha-form. The minor beta-form arises as a conse quence of the lack of glycosylation at Asn329. Although the functional role of Asn329 has been investigated by in vitro mutagenesis, until n ow no naturally occurring mutations have been reported at this site. W e describe here the case of two identical twin sisters compound hetero zygous for two novel PC mutations: Cys78 --> Stop inherited from the m aternal side and Asn329 --> Thr inherited from the paternal side, asso ciated with the presence of only the beta-form of PC in plasma. The Cy s78 --> Stop substitution is predicted to abolish PC synthesis from on e allele, whereas the Asn329 --> Thr substitution results in the reduc ed synthesis of a beta PC variant with decreased functional activity. PCN329T from the two monovular twin sisters was purified and its activ e form APC(N329T) was assessed for its ability to inactivate factor Va . Whereas no differences were observed between the activation rates of normal PC and PCN329T, APC(N329T) inactivated human factor Va with a rate slower than the normal APC. This is the first report of a PC defe ct involving glycosylation of the molecule. This defect results in the presence of only the beta-form of PC in human plasma and is responsib le for the reduced anticoagulant activity observed. (C) 1996 by The Am erican Society of Hematology.