Bernard-Soulier syndrome is a rare congenital platelet disorder that affects a surface membrane
adhesion receptor,
glycoprotein (GP) Ib-V-IX. Both the genetic defects and the
bleeding diatheses associated with the syndrome are heterogeneous due, in part, to the complexity of the involved receptor which consists of four different members, GPs: Ib alpha-Mr 143 K (contains the
von Willebrand factor-binding site), Ib beta-Mr 22 K, V-Mr 83 K and IX-
Mr 20 K. We studied a kindred that includes a 40 year-old man with severe
Bernard-Soulier syndrome: life-threatening gastrointestinal
bleeding,
thrombocytopenia, giant platelets and absent
ristocetin-dependent platelet aggregation. By Southern blotting, PCR amplification/sequencing, hetero-duplex analysis, and allele-specific
oligonucleotide hybridization, the Ib-V-IX genes were analyzed, and the molecular genetic defect was defined as a one-base deletion in the GPIb alpha gene, involving an
adenine of
codon 19. The mutation, K19R, homozygous in the propositus and heterozygous in the available unaffected relatives, leads to a frame shift in
codons 19-21 and a
premature stop codon after
codon 21. No functional GPIb alpha can be produced from the mutant allele, implying that the platelets of the affected patient lack all GPIb alpha. Within the spectrum of
Bernard-Soulier syndrome, this patient's disorder exemplifies a severe or "classic" extreme; an "experiment of Nature" that illustrates the effect of a complete deficiency of the
ligand-binding chain (GPIb alpha) of the GPIb-V-IX receptor.