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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4178-4187
R to Q Amino Acid Substitution in the GFFKR Sequence of the
Cytoplasmic Domain of the Integrin  IIb Subunit in a
Patient With a Glanzmann's Thrombasthenia-Like Syndrome
O. Peyruchaud,
A.T. Nurden,
S. Milet,
L. Macchi,
A. Pannochia,
P.F. Bray,
N. Kieffer, and
F. Bourre
From The UMR 5533 CNRS, Hôpital Cardiologique,
Pessac, France; The Division of Hematology, Department of Medicine, The
Johns Hopkins University School of Medicine, Baltimore, MD; The
Laboratoire Franco-Luxembourgeois de Recherche Biomédicale,
Centre Universitaire, Luxembourg; and The Dipartimento di Medicina ed
Oncologia Sperimentale, Sezione de Ematologia, University of
Turin, Turin, Italy.
The integrin  IIb 3 mediates platelet
aggregation through its fibrinogen and adhesive protein-binding
properties. Particular interest concerns the role of the cytoplasmic
domains of IIb and 3. We now report the
molecular analysis of IIb3 from a patient
with a Glanzmann's thrombasthenia-like syndrome for whom the principal
characteristics are an approximate 50% total platelet content of
IIb3 but with a much lower proportion in
the surface pool (Hardisty et al, Blood 80:696, 1992).
Polymerase chain reaction (PCR) single-strand conformational
polymorphism and DNA sequencing showed a heterozygous mutation giving
rise to amino acid substitution R995 to Q in the GFFKR
sequence of the cytoplasmic domain of IIb. Reverse
transcriptase-PCR and polymorphism analysis only detected mRNA for the
mutated allele of the IIb gene and a single allele of
the 3 gene in his platelets, suggesting other
unidentified defects. Site-directed mutagenesis followed by transient
expression of the mutated IIb together with wild-type
3 in Cos-7 cells resulted in a markedly decreased
expression of the complex at the cell surface when compared with cells
transfected with wild-type IIb and 3.
Flow cytometry with PAC-1 and a stable Chinese hamster ovary-transfected cell line showed that the mutated receptor was not
locked into a high activation state, although it became so in the
presence of the activating antibody, anti-LIBS6. This is the first
reported natural mutation in the highly conserved GFFKR sequence of the
IIb cytoplasmic domain.
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