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(Received for publication, January 31, 1996, and in revised form, June 25, 1996)
From the Bernard-Soulier Syndrome (BSS) is a rare
congenital bleeding disorder due to absent or decreased expression of
the glycoprotein Ib-IX-V (GpIb-IX-V) receptor complex on the platelet
surface. To date, only mutations in GpIb
Volume 271, Number 36,
Issue of September 6, 1996
pp. 22076-22080
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Promoter Resulting in the
Bernard-Soulier Syndrome
,
,
Cardeza Foundation for Hematologic Research,
Department of Medicine, Jefferson Medical College of Thomas Jefferson
University, Philadelphia, Pennsylvania 19107 and the Divisions of
§ Human Genetics and Molecular Biology and
¶ Hematology, The Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania 19104
or GpIX have been reported
in patients with BSS. GpIb
differs from the other proteins in this
receptor in that the gene is more complex, and an alternative form is
expressed in cells of non-megakaryocytic lineage, including endothelial
cells. It appears that the megakaryocytic and endothelial cell mRNA
species are transcribed from different start sites and have different
proximal promoter regions. We have identified a patient with BSS who
has a deletion on one chromosome 22, resulting in velocardiofacial
syndrome. The GpIb gene has been mapped to this deleted (22q11.2)
region of chromosome 22. The patient has greatly reduced levels of
GpIb mRNA and no detectable platelet GpIb protein, suggesting
that his BSS results from a mutation in his remaining GpIb allele.
Sequence analysis revealed that the coding region of GpIb is normal,
but the 5
-upstream region contains a C to G transversion at base 
133
from the transcription start site used in megakaryocytes. The mutation
changes a GATA consensus binding site, disrupts GATA-1 binding to the
mutated site, and decreases promoter activity by 84%. Thus, in this
patient, Bernard-Soulier syndrome results from a deletion of one copy
of GpIb and a mutated GATA binding site in the promoter of the
remaining allele, resulting in decreased promoter function and GpIb
gene transcription.
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