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Variant Bernard-Soulier syndrome associated with a homozygous mutation in
the leucine-rich domain of glycoprotein IX
JM Clemetson, PA Kyrle, B Brenner and KJ Clemetson
Theodor Kocher Institute, University of Berne, Switzerland.
We describe a new variant of Bernard-Soulier syndrome. The patient (W.K.)
showed the classic bleeding symptoms together with absence of platelet
agglutination to restocetin plus von Willebrand factor, whereas aggregation
to ADP, collagen, and arachidonic acid was normal. Platelets were markedly
larger than normal and the patient had life- long thrombocytopenia.
Surface-labeling of the platelets and two- dimensional gel electrophoresis
showed reduced but detectable amounts of glycoprotein (GP) Ib-IX-V
present;however, there was markedly less GPIX (2% +/- 1% of normal) than
GPIb alpha, Ib beta, or V (7% +/- 2% of normal). This disproportion was
confirmed by Western blotting. Sequence analysis was performed after
polymerase chain reaction amplification of the coding region of the GPIX
and GPI b alpha genes from the patient. A point mutation (A-->G) was
found in GPIX converting 45Asn to Ser within the leucine-rich domain. No
mutations were found in GPIb alpha. Both alleles of GPIX contained the same
defect, which was confirmed by the appearance of a new cleavage site for
the restriction enzyme Fnu4HI. This substitution did not affect
glycosylation at the neighboring 44Asn as judged by the distribution on
two-dimensional gels but did appear to change the conformation of the
leucine-rich domain, thus reducing surface expression of the complex. The
relationship between GPIb and GPV was not affected, indicating that GPIX
does not regulate this. This homozygous mutation in GPIX indicates that,
among other possible functions, the leucine-rich domains present on all
components of GPIb- IX-V may play a role in the assembly and surface
expression of the complex.
Volume 84,
Issue 4,
pp. 1124-1131,
08/15/1994
Copyright © 1994 by The American Society of Hematology
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