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Single-strand conformation polymorphism analysis is a rapid and effective
method for the identification of mutations and polymorphisms in the gene
for glycoprotein IIIa
Y Jin, HC Dietz, A Nurden and PF Bray
Department of Medicine, Johns Hopkins University School of Medicine,
Baltimore, MD.
Glanzmann thrombasthenia (GT) is the most common inherited disorder of
platelets. Most of the molecular defects previously identified in GT have
been caused by point (or other small) mutations in the genes for
glycoprotein (GP) IIb or GPIIIa. We have used single-strand conformation
polymorphism (SSCP) analysis to rapidly identify single- base changes in
the GPIIIa gene. Using genomic DNA from normal individuals and patients
with GT, each GPIIIa exon and a short stretch of flanking intronic sequence
was amplified, heat-denatured, and separated in nondenaturing acrylamide
gels. Only those fragments with an abnormal migration pattern were isolated
and the nucleotide sequence determined. Using SSCP, we detected the
polymorphism in the HPA-1 (P1A) system and all three known silent
polymorphisms in the GPIIIa gene. Screening 14 GPIIIa exons from 5 patients
with GT, one mutant allele was identified. The nucleotide sequence of the
abnormal 240-bp SSCP fragment was determined and a G-->A substitution in
the splice donor site of exon iv was identified. Analysis of platelet RNA
resulting from this mutation showed two mRNA species: one contained a
deletion of exon iv, whereas the other had a 27-bp addition to exon iv due
to the use of a cryptic splice site in the downstream intron. Single-base
substitutions are the most common mutation in GT and often result in
abnormal mRNA splicing. SSCP is a rapid and sensitive technique for
identifying mutations or polymorphisms in the GPIIIa gene.
Volume 82,
Issue 8,
pp. 2281-2288,
10/15/1993
Copyright © 1993 by The American Society of Hematology
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