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Hematopoietic and immune development and cardiovascular genetics
Hematopoietic and immune development:
We identified Jkap/MKP-X - a gene that encodes a unique MAPK phosphatase. Jkap
specifically regulates the JNK pathway. Jkap may play a role in the enforcement of stem/progenitor
cell quiescence by amplifying TGF-β growth inhibition signaling. We have also isolated a gene,
Gtl3b, that is expressed in early mesodermal precursors destined for both vascular and
hematopoietic lineages. Using molecular inversion probe technology we have initiated a project to
characterize about 2000 single nucleotide polymorphisms in immune response regulatory genes. This
platform will then be used in clinical studies of variation in response to infection and vaccines.
Cardiovascular genetics:
Congenital heart defects occur in about 7 per 1000 live births. We are analyzing several clinical disorders
that provide specific routes to gene identification. More information about these projects is contained at our dedicated
website: www.cardiogene.org. One project focuses on the underlying basis
for CHARGE Association. CHARGE is a complex phenotype that involves the development of the eye, ear, cranial nerves, brain,
genitourinary system, and heart. We are conducting a mapping survey in affected children and their parents to look for
submicroscopic deletions. We have also cloned the breakpoint in a rare patient with CHARGE and balanced translocation. Screening
of the gene altered by this breakpoint in sporadic CHARGE cases is underway. The second class of disorders
that we are studying is called heterotaxy. These conditions are caused by disturbance in the establishment of the left-right body
axis. So far mutations in 4 genes have been identified as causing human heterotaxy using this sample set - ZIC3, ACVR2B, LEFTYA,
and CFC1/cryptic. Current efforts focus on the nodal-dependent signaling pathway that operates in the node and left lateral
plate mesoderm. Future studies will extend this into the node-specific functional pathways and the establishment of the midline.
We have also been studying a mouse knockout mutant in Zic3 as a model for human heterotaxy. Our goal is to place Zic3p into one or
more the critical pathways that are required for left right asymmetry. These studies have revealed an unexpected role for
ZIC3 in gastrulation. We are also studying the genetics of hypoplastic left heart, coarctation of the aorta, aortic stenosis, and
bicuspid aortic valve. Together these defects are called left ventricular outflow tract obstruction (LVOTO) defects. This phenotype
behaves as a typical "complex trait". We are examining the role of polymorphisms in candidate genes using linkage and
linkage/association study designs. Linkage analysis has identified a promising locus on Chromosome 15. A very large scale
association study is underway.
International HapMap project:
We are collaborating with Dr. Richard Gibbs and ParAllele Biosciences in the production of haplotype maps for Chromosome 12.
Our particular interest is in novel methods for haplotype inference and the selection of "tag SNPs" that can be used in future
linkage/association studies for human diseases.
Selected Publications
Belmont JW, Henkel-Tigges J, Chang SMW, Wager-Smith K, Kellems
RE, Dick JE, Magli MC, Phillips RA, Bernstein A, Caskey CT (1986) Expression of
human adenosine deaminase in murine hematopoietic progenitor cells following retroviral transfer.
Nature 322:385-387.
Allen RC, Zoghbi HY, Moseley A, Rosenblatt H, Belmont JW (1992) Methylation of HpaII and
Hha I sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation.
American Journal of Human Genetics 51:1221-1239.
Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedell
MA, Edelhoff S, Disteche CM, Simoneaux DK, Fanslow WC, Belmont JW, Spriggs MK (1993) CD40 ligand gene
defects responsible for X-linked hyper-IgM syndrome. Science 259:990-993.
Cannon JP, Colicos SM, Belmont JW (1999) Gene trap screening using negative
selection: identification of two tandem, differentially expressed loci with potential hematopoietic
function. Developmental Genetics 25:49-63.
Kosaki K, Bassi MT, Kosaki R, Lewin M, Belmont JW, Schauer G, Casey B
(1999) Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine
genes implicated in left-right axis development. American Journal of Human Genetics
64:712-721.
Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont JW, Passage
M, Izykowski B, Phillips J, Doroshow R, Walot I, Hoft R, Neufeld EF (2001)
Enzyme-replacement therapy in mucopolysaccharidosis I. New England Journal of Medicine
344:182-188.
Lin F, Monaco G, Sun T, Liu J, Lin H, Stephens C, Belmont JW, Arlinghaus, RB (2001) BCR gene
expression blocks Bcr-Abl induced pathogenicity in a mouse model. Oncogene 20:1873-1881.
Purandare SM, Ware SM, Kwan KM, Gebbia M, Bassi MT, Deng JM, Vogel H,
Behringer RR, Belmont, JW, Casey B (2002) A complex syndrome of left-right axis, central nervous system and
axial skeleton defects in Zic3 mutant mice. Development 129:2293-2302.
Lalani SR, Stockton DW, Bacino C, Molinari LM, Glass NL, Fernbach SD, Towbin JA, Craigen WJ,
Graham JM Jr, Hefner MA, Lin AE, McBride KL, Davenport SL, Belmont JW (2003) Toward a genetic etiology
of CHARGE syndrome: I. A systematic scan for submicroscopic deletions. American Journal of Medical Genetics 118A:260-266.
Contact Information
- John W. Belmont, M.D., Ph.D.
- Department of Molecular and Human Genetics
- Baylor College of Medicine
- One Baylor Plaza T828
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-4634
- Fax: (713) 798-5386
- E-mail: jbelmont@bcm.edu
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