| Research Abstract |
The genetic basis for Glanzmann's thromboasthinenia (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 3 unique, proline-rich region at the location corresponding to the carboxy-terminal of the normal GPIIb a-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 transcriptional level expression of the present defective GPIIb molecule was significantly decreased (-6% of the control level). Because the precursor GPIIb molecule is assembled with GPIIIa in
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the endoplasmic reticulum (ER) and its processing, as well as stability, is dependent on the GPIIIa subunit, the defective GPIIb molecule may be a 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(-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 have proposed a classification of GT based on the biosynthetic pathway of the GPIIb-IIIa complex. The causative mutations of GT may be two categories in terms of the intracellular transport pathway of GP IIb-IIIa : preGolgi (preassembly) defects and postGolgi (postassembly) defects. If a mutation of the GPIIb or IIIa gene leads to the deficiency of mRNA (pretranslation defect) or misfolding of the subunit (posttranslation defect), formation of the stable complex in the ER or its transport to the Golgi complex may be impaired. Thus the Golgi defects result in the deficiency of GPIIb-IIIa on the platelet surface. In contrast, if a stable complex is formed and is transported to the Golgi, even the mutant heterodimer may be expressed comparably to the normal level (postGolgi defects). In the preGolgi-posttranslation defects, the mutant subunits may be rapidly degraded in the ER after binding to the molecular chaperones shch as Bip (binding protein). In the postGolgi defects, a part of the mutant complex may be sorted to the lysosomal degradation. In general, most cases of type I and type II GT may be caused primarily by the preGolgi defects and some cases of type II and variants by the post Golgi defects. Less
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