The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis ...The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.展开更多
Identifying genetic variants that contribute to phenotypic variation is expected to provide insights into the etiology of complex traits. Here we show how combining genetic mapping in an outbred population of rats wit...Identifying genetic variants that contribute to phenotypic variation is expected to provide insights into the etiology of complex traits. Here we show how combining genetic mapping in an outbred population of rats with sequence data from the progenitors of the population made it possible to identify causal variants and genes for a large number of phenotypes. We identified 355 genomic loci contributing to 122 measures relevant to six models of disease, including fear-related behaviors and experimental autoimmune encephalomyelitis. At 35 of those loci we identified the responsible gene, and in some cases, the responsible variant.展开更多
Correlative light electron microscopy prefers single probes with stable performance in both optical and electron microscopy.Now researchers have shown how to harness gold nanoparticles featuring exceptional photostabi...Correlative light electron microscopy prefers single probes with stable performance in both optical and electron microscopy.Now researchers have shown how to harness gold nanoparticles featuring exceptional photostability and four-wave-mixing nonlinearity to realize a new correlation imaging approach.展开更多
基金supported by funding from the Medical Research Council (MRC) through the WIMM Strategic Alliance (G0902418 and MC_UU_12025) and to E. Y.J. (G9900061),the Department of Health, UK, Quality, Improvement, Development and Initiative Scheme (QIDIS) (AOMW)the Wellcome Trust (Project Grant 093329 to AOMW and SRFT+8 种基金Investigator Award 102731 to AOMWgrant 090532/Z/09/Z supporting the Wellcome Trust Centre for Human Genetics)supported by the Crohn’s & Colitis Foundation of America (CCFA)the Leona M. and Harry B. Helmsley Charitable Trustfunded by the NIHR Oxford Biomedical Research Centresupported by the Deutsche Forschungsgemeinschaft (SCHW1730/1-1)supported by the Deutsche Forschungsgemeinschaft (DFG), Bonn (grant number SFB841 to F.K., D.S.-A., and S.R.-J.SFB877 to S.R.-J.)the Cluster of Excellence “Inflammation at Interfaces” to S.R.-J.
文摘The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.
文摘Identifying genetic variants that contribute to phenotypic variation is expected to provide insights into the etiology of complex traits. Here we show how combining genetic mapping in an outbred population of rats with sequence data from the progenitors of the population made it possible to identify causal variants and genes for a large number of phenotypes. We identified 355 genomic loci contributing to 122 measures relevant to six models of disease, including fear-related behaviors and experimental autoimmune encephalomyelitis. At 35 of those loci we identified the responsible gene, and in some cases, the responsible variant.
文摘Correlative light electron microscopy prefers single probes with stable performance in both optical and electron microscopy.Now researchers have shown how to harness gold nanoparticles featuring exceptional photostability and four-wave-mixing nonlinearity to realize a new correlation imaging approach.
