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An exon 28 mutation resulting in alternative splicing of the glycoprotein
IIb transcript and Glanzmann's thrombasthenia
S Iwamoto, E Nishiumi, E Kajii and S Ikemoto
Department of Legal Medicine and Human Genetics, Jichi Medical School,
Tochigi, Japan.
The alternatively spliced from mRNA of platelet glycoprotein IIb (GPIIb)
with a deletion of exon 28 (GPIIb-28) has been isolated from the HEL cell
cDNA library. The defective expression on the surface of DNA cotransfected
COS-1 cells with GPIIb-28 and GPIIIa cDNAs was described in an earlier
report. We studied siblings with Glanzmann's thrombasthenia who expressed
only the GPIIb-28 mRNA in their platelets. Flow cytometry showed that the
patients' platelets failed to bind GPIIb/IIIa complex-specific and
GPIIb-specific monoclonal antibody. Western blotting showed that the
patients' platelets had defective GPIIb and have trace amounts of GPIIIa.
Sequence analysis was performed after polymerase chain amplification of the
patients' GPIIb and GPIIIa mRNAs. The patients' GPIIb cDNA had a deletion
of the exon 28 nucleotides. The polymerase chain reaction (PCR) from exon
27 to 29 showed that the GPIIb-28 mRNA was 3% +/- 1.6% of the normally,
spliced form in control platelets, and 61% in the megakaryoblastic cell
line UT- 7. The patients' platelets showed only the GPIIb-28. Family study
and quantitative PCR studies showed that these patients were compound
heterozygotes of two GPIIb gene defects. The father's allele is described
in this report and involves skipping exon 28 secondary to a base
substitution at codon Gln948, CAG-->TAG. The mother's allele appears to
involve decreasing GPIIb mRNA levels in platelets. Our results indicate
that the GPIIb-28 is not expressed on platelet membranes as a stable
GPIIb/IIIa heterodimer or left as a monomer in platelets. Our studies
confirm the previous data observed in COS-1 cells expressing recombinant
GPIIb-28.
Volume 83,
Issue 4,
pp. 1017-1023,
02/15/1994
Copyright © 1994 by The American Society of Hematology
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