The Genetic Defect in Two Well-Studied Cases of Bernard-Soulier Syndrome: A Point Mutation in the Fifth Leucine-Rich Repeat of Platelet Glycoprotein Iba

Bernard-Soulier syndrome (B&) is a rare congenital bleeding disorder caused by abnormal giant platelets. thrombocytopenia, and defective glycoprotein (GP) Ib-V-IX, the adhesion receptor for von Willebrand factor (vWF). This report describes the molecular defect in two related individuals with well-established B-Ss whose platelets exhibit decreased GPb-IX and normal GPV on their surfaces. The GPlbV-IX genes of the two patients were analyzed by Southern blotting, hetero-duplex analysis, and polymerase chain reaction (PCR) ampliiication/sequencing. A point mutation was found in codon 129 of the GPlba gene that results in the substitution of proline for leucine in the first position of the fifth leucine-rich glycoprotein repeat of the mature gene product. The mutation (C=: leucine, wild-type t o CU2proline, mutant) eliminates a Sac I restriction site, facilitating analysis of the mutation in the propositi (both homozygotes), unaffected family members (8 heterozygotes and 8 wild-type), and 58 normal controls (116 wild-type alleles). The status of the genomes was confirmed by the sequencing