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-IX-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 subunits of the GPIb-IX-V complex (GPIb alpha, Ib beta, IX and V) are molecular products of different genes. Several point mutations and deletions 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 defect of GPIb beta. We investigated the molecular basis of another case of BSS with a deficient expression of GPIX, as detected by immunofluorescence studies. After amplification of the entire GPIX coding region, nucleotide sequence analysis showed a homozygous single point mutation predicting a phenylalanine to serine substitution at position 55 of the mature GPIX within its unique leucine-rich repeat. By allele-specific oligonucleotide hybridization we confirmed the homozygosity of the patient as well as the carrier state of two out of three of his children studied. Although the parents of the patient, who were first cousins, were no longer alive and thus not available for study, we speculate that the molecular defect observed in the proband was inherited from both parents, who probably were heterozygous for this GPIX gene defect. This study confirms that BSS may be caused by many different subtle molecular defects that often prevent the assembly and expression of a functional GPIb-IX-V complex.