A PHENYLALANINE-55 TO SERINE AMINO-ACID SUBSTITUTION IN THE HUMAN GLYCOPROTEIN-IX LEUCINE-RICH REPEAT IS ASSOCIATED WITH BERNARD-SOULIER-SYNDROME

The platelet membrane glycoprotein (GP) Ib-M-V complex, the major von Willebrand factor receptor on platelets, is absent or dysfunctional in patients with the Bernard-Soulier syndrome (BSS). The four single sub units of the GPIb-IX-V complex (GPIb alpha, Ib beta, IX and V) are mol ecular products of different genes. Several point mutations and deleti ons affecting the GPIb alpha gene have been identified as the cause of BSS, whilst in four BSS families a GPIX gene defect has been reported . Moreover, a single case of BSS has been associated with a genetic de fect of GPIb beta. We investigated the molecular basis of another case of BSS with a deficient expression of GPIX, as detected by immunofluo rescence studies. After amplification of the entire GPIX coding region , nucleotide sequence analysis showed a homozygous single point mutati on predicting a phenylalanine to serine substitution at position 55 of the mature GPIX within its unique leucine-rich repeat. By allele-spec ific oligonucleotide hybridization we confirmed the homozygosity of th e patient as well as the carrier state of two out of three of his chil dren studied. Although the parents of the patient, who were first cous ins, were no longer alive and thus not available for study, we specula te that the molecular defect observed in the proband was inherited fro m both parents, who probably were heterozygous for this GPIX gene defe ct. This study confirms that BSS may be caused by many different subtl e molecular defects that: often prevent the assembly and expression of a functional GPIb-IX-V complex.