We report here the genetic basis of
Bernard-Soulier syndrome in a compound heterozygote for two mutant
glycoprotein (GP) Ib alpha alleles. One allele contained a novel four base-pair deletion (TGAG) that eliminated the last base of the
codon for Ser39 (AGT) and the entire
codon for Glu40 (GAG), causing a reading frame shift that yielded a stretch of 51
amino acids before a
premature stop codon. The other allele also contained a frame-shift mutation, caused by deletion of the last two bases of the
codon for Tyr492 (TAT). This allele produced a truncated
glycoprotein Ib alpha that, although not expressed on the surface of the patient's platelets, was detectable in the plasma. The second allele has been identified previously by our group and other investigators as the cause of
Bernard-Soulier syndrome in patients of northern European ancestry. This allele carried a haplotype identical to those of the previously reported cases, with the following polymorphic markers: two tandem repeats in the VNTR region, C at
nucleotide -5 from the ATG
start codon and a substitution of G for A in the third base for
codon Arg342. These findings suggest that this particular Bernard-Soulier mutation occurred once on the background of a rare haplotype and has spread throughout the northern European population.