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Bernard-Soulier syndrome Kagoshima: Ser 444-->stop mutation of
glycoprotein (GP) Ib alpha resulting in circulating truncated GPIb alpha
and surface expression of GPIb beta and GPIX [see comments]
S Kunishima, H Miura, H Fukutani, H Yoshida, K Osumi, S Kobayashi, R Ohno and T Naoe
Department of Internal Medicine, Nagoya University Branch Hospital, Japan.
The platelet membrane glycoprotein (GP)Ib/IX complex is composed of three
polypeptides, GPIb alpha, GPIb beta, and GPIX, and functions as a platelet
receptor for von Willebrand factor. All three subunits are reported to be
requisite for efficient surface expression of the complex. The absence of
the GPIb/IX complex on platelet membrane is the hallmark of a congenital
qualitative platelet disorder, termed the Bernard-Soulier syndrome (BSS).
We describe here the molecular basis of a novel variant phenotype of BSS in
a female patient, designated as BSS Kagoshima. Her platelets completely
lacked the surface expression of GPIb alpha, but expressed a residual
amount of GPIb beta and GPIX. Unexpectedly, her platelets and plasma
contained a truncated GPIb alpha polypeptide with an apparent molecular
weight of 116 kD (under nonreducing conditions). The amounts of truncated
protein were 23% and 60% of the normal values in platelets and plasma,
respectively. The abnormal protein contained a normal amount of sialic acid
as demonstrated by digestion with neuraminidase. DNA sequencing analysis
showed a homozygous single nucleotide substitution from the serine codon
(TCA) to a nonsense codon (TAA) at residue 444 in the GPIb alpha gene. The
mutant gene generated a truncated GPIb alpha molecule lacking the
transmembrane region and cytoplasmic tail. Her parents were heterozygotes
for the mutation. These findings suggest that this type of truncated GPIb
alpha was produced, normally glycosylated, and subsequently secreted into
the plasma. Furthermore, the truncated GPIb alpha might be associated with
the process of the surface expression of incomplete GPIb/IX complex, GPIb
beta and GPIX.
Volume 84,
Issue 10,
pp. 3356-3362,
11/15/1994
Copyright © 1994 by The American Society of Hematology
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