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Itzhaki I Maizels L Huber I Zwi-Dantsis L Caspi O Winterstern A Feldman O Gepstein A Arbel G Hammerman H Boulos M Gepstein L 《Nature》2011,471(7337):225-229
The ability to generate patient-specific human induced pluripotent stem cells (iPSCs) offers a new paradigm for modelling human disease and for individualizing drug testing. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies. 相似文献
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Novel mutations target distinct subgroups of medulloblastoma 总被引:1,自引:0,他引:1
Robinson G Parker M Kranenburg TA Lu C Chen X Ding L Phoenix TN Hedlund E Wei L Zhu X Chalhoub N Baker SJ Huether R Kriwacki R Curley N Thiruvenkatam R Wang J Wu G Rusch M Hong X Becksfort J Gupta P Ma J Easton J Vadodaria B Onar-Thomas A Lin T Li S Pounds S Paugh S Zhao D Kawauchi D Roussel MF Finkelstein D Ellison DW Lau CC Bouffet E Hassall T Gururangan S Cohn R Fulton RS Fulton LL Dooling DJ Ochoa K Gajjar A Mardis ER Wilson RK Downing JR Zhang J Gilbertson RJ 《Nature》2012,488(7409):43-48
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development. 相似文献
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The genome of the mesopolyploid crop species Brassica rapa 总被引:21,自引:0,他引:21
Wang X Wang H Wang J Sun R Wu J Liu S Bai Y Mun JH Bancroft I Cheng F Huang S Li X Hua W Wang J Wang X Freeling M Pires JC Paterson AH Chalhoub B Wang B Hayward A Sharpe AG Park BS Weisshaar B Liu B Li B Liu B Tong C Song C Duran C Peng C Geng C Koh C Lin C Edwards D Mu D Shen D Soumpourou E Li F Fraser F Conant G Lassalle G King GJ Bonnema G Tang H Wang H Belcram H Zhou H Hirakawa H Abe H Guo H Wang H Jin H Parkin IA Batley J Kim JS Just J Li J Xu J Deng J Kim JA Li J Yu J Meng J Wang J Min J 《Nature genetics》2011,43(10):1035-1039
We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops. 相似文献
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