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Double heterozygosity for mutations in the platelet glycoprotein IX gene in
three siblings with Bernard-Soulier syndrome
SD Wright, K Michaelides, DJ Johnson, NC West and EG Tuddenham
Department of Haematology, Royal Postgraduate Medical School, Hammersmith
Hospital, London, UK.
Bernard-Soulier syndrome (BSS) giant platelets have defective and/or
deficient glycoprotein (GP) Ib/IX complexes, causing absent ristocetin-
induced aggregation, defective interaction with von Willebrand factor,
morphologic abnormality, and a clinical bleeding tendency. Recently several
mutations have been described in the platelet GPIb alpha gene in
individuals exhibiting the BSS phenotype. We have studied a family with
classical BSS, and have excluded lesions at the GPIb alpha locus by
restriction fragment length polymorphism linkage analysis. Analysis of the
genes for two other components of the platelet GPIb:IX complex, namely GPIb
beta and GPIX, showed two different missense mutations in the coding region
of the GPIX gene: an A-->G transition in codon 21 results in conversion
of an aspartic acid to glycine and an A-->G change in codon 45 converts
an asparagine residue to serine. Three affected individuals are doubly
heterozygous for these mutations, which alter conserved residues in or
flanking the GPIX leucine-rich glycoprotein motif. Both mutations create
new recognition sites for the enzyme Fnu 4H1; therefore, this enzyme was
used to screen 60 normal subjects (120 alleles). Neither mutation was
detected in any subject other than direct relatives of the affected
individuals. Although low levels of GPIb were demonstrable by both flow
cytometry and immunoblot analysis in an affected individual's platelets,
there was no evidence of GPIX immunoreactivity. We propose that expression
of abnormal GPIX prevents stable assembly of the GPIb/IX complex, causing
BSS in the doubly heterozygous individuals in this family.
Volume 81,
Issue 9,
pp. 2339-2347,
05/01/1993
Copyright © 1993 by The American Society of Hematology
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