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Mutation of leucine-57 to phenylalanine in a platelet glycoprotein Ib alpha
leucine tandem repeat occurring in patients with an autosomal dominant
variant of Bernard-Soulier disease
JL Miller, VA Lyle and D Cunningham
Department of Pathology, SUNY Health Science Center, Syracuse 13210.
The primary sequences of the three individual glycoprotein (GP) chains,
GPIb alpha, GPIb beta, and GPIX, comprising the normal platelet GPIb/IX
receptor for von Willebrand factor (vWF) have recently been determined,
opening the possibility for characterization of disorders of this receptor
at the molecular level. The presence of a leucine tandem repeat in each of
these chains is of particular interest, because such repeats may be
involved in associations between polypeptide segments. We now report an
autosomal dominant variant of Bernard-Soulier disease associated with the
heterozygous substitution of phenylalanine for a highly conserved leucine
residue within the GPIb alpha leucine tandem repeat. Affected individuals
experienced a moderate bleeding tendency, thrombocytopenia, and an
increased mean platelet volume. Platelet aggregation was decreased only in
response to ristocetin or to asialo- vWF. The kd for 125I-vWF binding to
patients platelets was significantly increased over control values at 0.5
mg/mL ristocetin, but was normal at 1.0 or 1.5 mg/mL ristocetin. While
sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed an
essentially normal complement of all components of the GPIb/IX complex, a
minor amount of a putative proteolytic fragment was identified that
migrated faster than GPIb and was immunoreactive with polyclonal anti-GPIb
alpha antibody, but not with a monoclonal antibody directed against the
45-Kd amino-terminal region of GPIb alpha. However, because the great
majority of patient GPIb alpha comigrates with normal GPIb alpha, the major
functional abnormalities of the patient platelets are most likely a
consequence of the altered structure of the nonproteolyzed protein. Full
concordance within the studied family between phenotypic expression and a
heterozygous single nucleotide substitution in genomic DNA coding for a
phenylalanine in place of the wild-type leucine at residue 57 of the mature
GPIb alpha, absence of this substitution in 266 alleles from the normal
population, and the lack of any other abnormality of patient DNA throughout
the entire coding sequence for GPIb alpha provide strong support that this
substitution may constitute a pathologic point mutation responsible for the
observed phenotypic abnormalities. While the roles that leucine tandem
repeats may normally play within the GPIb/IX complex are not yet known, the
perturbation of such a repeat in GPIb alpha may impair interaction with
other components of the complex and/or with the binding of vWF.
Volume 79,
Issue 2,
pp. 439-446,
01/15/1992
Copyright © 1992 by The American Society of Hematology
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