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Molecular basis for Glanzmann's thrombasthenia (GT) in a compound
heterozygote with glycoprotein IIb gene: a proposal for the classification
of GT based on the biosynthetic pathway of glycoprotein IIb-IIIa complex
A Kato, K Yamamoto, S Miyazaki, SM Jung, M Moroi and N Aoki
First Department of Internal Medicine, Tokyo Medical and Dental University,
Japan.
The genetic basis for Glanzmann's thrombasthenia (GT) was elucidated on a
compound heterozygote with glycoprotein (GP)IIb gene: an opal mutation at
the end of exon 17 (CGA----TGA) results in only a trace amount of GPIIb
mRNA, and a splicing mutation at the acceptor site of exon 26 (CAG----GAG)
causes an in-frame, exon skipping process from exon 25 to 27. This aberrant
transcript encodes a single-chain polypeptide characterized by a 42-amino
acid deletion, which includes the proteolytic cleavage site(s) and a
unique, proline-rich region at the location corresponding to the
carboxyl-terminal of the normal GPIIb alpha-chain. These characteristics
are shared by a previously reported defective GPIIb molecule, which is
neither assembled with GPIIIa nor transported to the cellular surface.
Despite its normal transcription level, expression of the present defective
GPIIb molecule was significantly decreased (approximately 6% of the control
level). Because the precursor GPIIb molecule is assembled with GPIIIa in
the endoplasmic reticulum (ER) and its processing, as well as stability, is
dependent on the GPIIIa subunit, the defective GPIIb molecule may be
rapidly degraded by the intrinsic quality control system of the ER due to
its inability to form a stable heterodimer complex as a consequence of its
misfolded structure. Although we did not confirm that the GPIIIa genes of
this individual were normal, GPIIIa may be secondarily decreased
(approximately 11% of control), because a large part of it could not be
complexed, making it vulnerable to proteolysis. To elucidate the molecular
basis for GT, we propose here a classification of GT based on the
biosynthetic pathway of the GPIIb-IIIa complex.
Volume 79,
Issue 12,
pp. 3212-3218,
06/15/1992
Copyright © 1992 by The American Society of Hematology
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