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Identification of an abnormal gene for the GPIIIa subunit of the platelet
fibrinogen receptor resulting in Glanzmann's thrombasthenia
PF Bray and MA Shuman
Department of Medicine, University of California, San Francisco 94143-
0128.
The platelet fibrinogen receptor, which is composed of glycoproteins IIb
(GPIIb) and IIIa (GPIIIa), belongs to a large family of receptors that
participate in a multitude of biologically important adhesive interactions.
Platelets from most patients with the autosomal recessive bleeding
disorder, Glanzmann's thrombasthenia, are deficient in GPIIb and GPIIIa. We
have used cDNA probes to analyze the GPIIb and GPIIIa genes in four
patients from three kindreds with Glanzmann's thrombasthenia. Southern
analysis of their DNA was identical to that observed in normals when probed
with a full-length GPIIb cDNA or a 3' GPIIIa cDNA. However, in one family,
a 5' 2.0 kb GPIIIa cDNA identified abnormal DNA fragments in the father and
two affected siblings' genes. A series of restriction digests resulting in
small genomic fragments were probed with portions of the 5' 2.0 kb GPIIIa
cDNA and indicated that the abnormal sequences are flanked by normal
fragments of the GPIIIa gene. To analyze further the genetic defect in this
family, RNA was prepared from their platelets. Northern analysis revealed
normal levels of GPIIb mRNA compared to control platelets. We were unable
to identify GPIIIa mRNA of any size in the clinically affected family
members. We also identified an EcoRI restriction fragment length
polymorphism (RFLP) that permitted carrier status determination in the
clinically unaffected siblings. These studies indicate that Glanzmann's
thrombasthenia can be caused by heterogeneous defects in the GPIIIa gene.
Furthermore, we have shown that platelets can be used to characterize
normal and abnormal GPIIIa and GPIIb mRNA, and RFLPs may be used to
determine the carrier status in some families with Glanzmann's
thrombasthenia. The specific gene abnormality in this family appears to
represent an example of an insertional mutation resulting in a human
disease.
Volume 75,
Issue 4,
pp. 881-888,
02/15/1990
Copyright © 1990 by The American Society of Hematology
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