Scientists and doctors continue to find themselves baffled by Kawasaki disease (KD), an inflammatory disorder that represents the leading cause of pediatric heart problems in the developed world. “The cause of KD has remained unknown for more than 40 years since the first description of the disease by Dr. Kawasaki, and so there is no evidence-based therapeutic strategy,” says Yoshihiro Onouchi of the RIKEN Center for Genomic Medicine in Yokohama.
Onouchi has partnered with other scientists in Japan and the United States to identify chromosomal regions containing genes potentially associated with this condition, uncovering strong evidence that KD arises in part from improper regulation of the immune system. Based on this hypothesis, he and his colleagues recently examined loci within chromosomal region 4q35, which contains a diverse array of genes relevant to this process1.
The researchers were especially interested in the gene encoding caspase-3 (CASP3), an enzyme that participates in the initiation of programmed cell death and thereby helps to mitigate the extent of T cell-mediated immune responses. By comparing data from a cohort of Japanese individuals affected with KD relative to their unaffected counterparts, they were able to identify more than two dozen sequence variations near CASP3 that appear to preferentially associate with disease onset.
Functional analysis of the gene revealed the presence of an ‘enhancer’, a stretch of DNA where regulatory proteins can bind to help ratchet up expression levels, surrounding one of the variants identified in this initial screen. The researchers determined that the genomic sequence alteration linked with KD appears to impair enhancer binding by the transcriptional regulator nuclear factor of activated T cells (NFAT), and this reduced NFAT binding in turn leads to significantly reduced CASP3 expression. Importantly, this variant is also significantly associated with disease susceptibility in European populations.
Onouchi and colleagues have previously identified another KD-associated variation (or SNP) in the gene encoding inositol 1,4,5-trisphosphate 3 kinase-C (ITPKC), an enzyme that downregulates a T cell signaling cascade in which calcium ion (Ca2+) flux is coupled with NFAT activation2. In combination, these findings suggest that NFAT may offer a promising drug target. “The calcineurin enzyme plays a key role in the Ca2+/NFAT pathway, and we are now interested in the potential of calcineurin inhibitors like cyclosporin A as a therapeutic option,” says Onouchi. “Our team is now collaborating with several medical institutes in Japan in an attempt to evaluate the effectiveness of cyclosporin A on refractory KD cases.”
The corresponding author for this highlight is based at the Laboratory for Cardiovascular Disease, RIKEN Center for Genomic Medicine
Journal information1. Onouchi, Y., Ozaki, K., Burns, J.C., Shimizu, C., Hamada, H., Honda, T., Terai, M., Honda, A., Takeuchi, T., Shibuta, S. et al. Common variants in CASP3 confer susceptibility to Kawasaki disease. Human Molecular Genetics published online 10 May 2010 (doi: 10.1093/hmg/ddq176)
2. Onouchi, Y., Gunji, T., Burns, J.C., Shimizu, C., Newburger, J.W., Yashiro, M., Nakamura, Y., Yanagawa, H., Wakui, K., Fukushima, Y. et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nature Genetics 40, 35–42 (2008)
gro-pr | Research asia research news
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
05.12.2016 | Power and Electrical Engineering
05.12.2016 | Materials Sciences
05.12.2016 | Power and Electrical Engineering