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
Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences