CURRENT CLINICAL INTERESTS
Disorders of hemostasis and thrombosis, VWD, ITP
CURRENT RESEARCH
INTERESTS
Modifiers of von Willebrand Factor (VWF), von Willebrand Diseases (VWD),
vascular endothelial gene expression, familial ITP
RESEARCH DESCRIPTION
The regulation of endothelial cell gene expressio plays
a central role in maintaining hemostatic balance, and we are just
beginning to understand the key sequence elements responsible for the
control of the endothelial gene expression program. The inbred
mouse strain, RIIIS/J, was found to have an endothelial-specific
regulatory mutation in the gene encoding an N-acetylgalactosaminyltransferase,
B4GALNT2. This regulatory mutation, termed Mvwf1,
directs a tissue-specific switch in the B4galnt2
gene expression program from intestinal epithelium to
vascular endothelium. The endothelial expression of B4GALNT2 results
in aberrant glycosylation of VWF and accelerated VWF clearance from
circulation, causing a phenotype very similar to Type 1 VWD in humans.
The ectopic expression of B4galnt2
in vascular endothelial cells results in aberrant post-translational
modification of VWF, leading to accelerated clearance. We seek to
characterize the mutation responsible for this remarkable
tissue-specific switch in gene expression. Using comparative
sequence analysis and BAC transgenic studies we have identified a
genomic region distal to the B4galnt2
structural gene that likely contains the regulatory elements necessary
for tissue-specific B4galnt2
gene expression. We are now recombineering BACs to pinpoint the
regions critical for endothelial cell-specific gene regulation for
further study. During the course of these studies we also found
that Mvwf1 exists in
some contemporary wild mouse populations. We are investigating
if this low-VWF Mvwf1 phenotype
could be maintained due to selective pressure.
Idiopathic thombocytopenic purpura (ITP) is
defined by the presence of thrombocytopenia in the absence of an
identifiable secondary cause. An autoimmune process has been
strongly implicated, yet the molecular mechanisms responsible for ITP
are unknown and treatment remains largely empiric. Although ITP
is generally considered a sporadic disorder, the possibility that
there can be a familial predisposition to isolated ITP has been
raised. Associations between ITP and polymorphisms in genes
involved in immune response have been described, but these
associations have not been proven causative. Rarely, ITP is
associated with other autoimmune cytopenias, but the etiology of
associated cytopenias is also unknown, and therapy is similar to the
management of isolated ITP. Our goal is to identify gene(s)
involved in the pathogenesis of familial ITP. We initiated this
study when we were contacted about a large family with familial ITP,
and several family members also have autoimmune hemolytic anemia.
We aim to study this family and recruit similarly affected
families in order to identify candidate genes involved in ITP.
We speculate that genes identified in this study could be involved in
key pathways involved in humoral immunity and the regulation of
tolerance, but platelet-specific phenotypes or novel genes with
previously unknown function may also be discovered.
SELECTED
PUBLICATIONS
Johnsen JM,
Teschke M, Pavlidis P, McGee BM, Tautz D, Ginsburg D, and Baines JF.
Selection on cis-regulatory
variation at B4galnt2 and its influence on von Willebrand Factor in
house mice. Molecular
Biology and Evolution
26(3):567-578, 2009.
Johnsen J, Levy G, Westrick R, Tucker P, Ginsburg D. The
endothelial specific regulatory mutation Mvwf1,
is a common mouse founder allele. Mammalian Genome
19:32-40, 2008.
|
