CURRENT CLINICAL INTERESTS
Disorders of hemostasis and thrombosis, VWD, ITP, blood group systems
Modifiers of von Willebrand
Factor (VWF), von Willebrand Diseases (VWD), vascular endothelial gene
expression, familial ITP, pregnancy-related hematologic disorders,
glycan-mediated host-microbe interactions, blood group
The regulation of endothelial
cell gene expression plays a central role in maintaining hemostatic
balance, and we do not yet fully 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 von Willebrand Factor (VWF) and accelerated VWF clearance from
circulation, causing a phenotype very similar to Type 1 von Willebrand
Disease (VWD) in humans. We are now using a variety of
molecular techniques to characterize the mechanism underlying this
unique tissue-specific switch in gene expression.
The Mvwf1 allele exists in
some contemporary wild mouse populations, where there are striking
signatures of selection at the B4galnt2
locus. We are studying the
evolution of this allele in the genus Mus,
where we have found strong evidence of long-term balancing selection.
In addition to the role VWF could play in the maintenance of Mvwf1
in natural populations, we hypothesize that a favorable phenotype may
be conferred to wild mice by loss of B4galnt2
bowel expression. We
are now exploring the interaction of microbes with B4galnt2-sugars
and other carbohydrate blood groups (H and ABO) at the mucosal
Levels of the clotting protein,
von Willebrand Factor (VWF), increase during pregnancy and likely play
a role in the significantly increase in risk of clotting observed
during pregnancy and in the post-partum period.
The life-threatening pregnancy-related disorders pre-eclampsia/eclampsia
and HELLP exhibit even higher levels of VWF.
We are studying VWF changes during normal pregnancy, and plan
to expand these studies to complicated pregnancies with the goal of
developing diagnostic tools or identifying novel therapeutic targets
for pregnancy-related disorders of hemostasis and thrombosis.
The human orthologue of the glycosyltransferase B4galnt2 confers the minor blood group antigen, Sda. Other carbohydrate blood group antigens have been implicated in altering VWF levels and possibly influencing risk for thrombosis and bleeding. We are taking a genetic approach to understand the biological significance of VWF glycosylation patterns by blood group glycosyltransferases, including Sda, ABO,and H.
Blood group antigens exhibit considerable diversity in human populations. We seek to deeply characterize the genetic diversity underlying blood group variation and to correlate these variants with susceptibility to disease, including bleeding and thrombosis.
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. Our goal is
to identify gene(s) involved in the pathogenesis of inherited ITP,
which may be implicated in the more common sporadic form of the
disease. 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.
JC Zimring, S Stowell, JM Johnsen, and JE Hendrickson. The Effect of Genetic, Epigenetic, and Environmental Factors on Alloimmunization to Transfused Antigens; Current Paradigms and Future Considerations. Transfusion Clinique et Biologique, June 6, 2012. (epub ahead of print) PMID:22682308
JC Zimring, JM Johnsen. Keeping the Kell away from immunity. Blood, Jun 7;119(23):5346-8, 2012. PMID:22679338
F, Kunzel S, Baines AC, Yee A, McGee BM, Backhed F, Baines JF, Johnsen
JM. Expression of the
glycosyltransferase B4galnt2 influences the intestinal microbiota in
mice. The ISME Journal
6(7):1345-55, 2012. PMID:22278669
Linnenbrink M, Johnsen
JM, Montero I, Brzezinksi CR, Harr
B, Baines JF. Long-term balancing selection at the blood-group related
gene B4galnt2 in the genus Mus (Rodentia; Muridae). Molecular
Biology and Evolution28(11):2999-3003, 2011. PMID:21652612
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,
JM, López JA. VWF secretion: what’s in a name? Blood, 112(4):926-7, 2008. PMID:18684873
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. PMID:18188647