排序方式: 共有31条查询结果,搜索用时 62 毫秒
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Bi-allelic inactivation of TCF1 in hepatic adenomas 总被引:9,自引:0,他引:9
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Spinazzola A Viscomi C Fernandez-Vizarra E Carrara F D'Adamo P Calvo S Marsano RM Donnini C Weiher H Strisciuglio P Parini R Sarzi E Chan A DiMauro S Rötig A Gasparini P Ferrero I Mootha VK Tiranti V Zeviani M 《Nature genetics》2006,38(5):570-575
The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice. 相似文献
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Cambon-Thomsen A Thorisson GA Mabile L Andrieu S Bertier G Boeckhout M Cambon-Thomsen A Carpenter J Dagher G Dalgleish R Deschênes M di Donato JH Filocamo M Goldberg M Hewitt R Hofman P Kauffmann F Leitsalu L Lomba I Mabile L Melegh B Metspalu A Miranda L Napolitani F Oestergaard MZ Parodi B Pasterk M Reiche A Rial-Sebbag E Rivalle G Rochaix P Susbielle G Tarasova L Thomsen M Thorisson GA Zawati MH Zins M;BRIF workshop group 《Nature genetics》2011,43(6):503-504
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KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron 总被引:1,自引:0,他引:1
Louis-Dit-Picard H Barc J Trujillano D Miserey-Lenkei S Bouatia-Naji N Pylypenko O Beaurain G Bonnefond A Sand O Simian C Vidal-Petiot E Soukaseum C Mandet C Broux F Chabre O Delahousse M Esnault V Fiquet B Houillier P Bagnis CI Koenig J Konrad M Landais P Mourani C Niaudet P Probst V Thauvin C Unwin RJ Soroka SD Ehret G Ossowski S Caulfield M;International Consortium for Blood Pressure 《Nature genetics》2012,44(4):456-60, S1-3
Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure. 相似文献
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Iva Simeonova Emmanuelle Huillard 《Cellular and molecular life sciences : CMLS》2014,71(20):4007-4026
Although our knowledge of the biology of brain tumors has increased tremendously over the past decade, progress in treatment of these deadly diseases remains modest. Developing in vivo models that faithfully mirror human diseases is essential for the validation of new therapeutic approaches. Genetically engineered mouse models (GEMMs) provide elaborate temporally and genetically controlled systems to investigate the cellular origins of brain tumors and gene function in tumorigenesis. Furthermore, they can prove to be valuable tools for testing targeted therapies. In this review, we discuss GEMMs of brain tumors, focusing on gliomas and medulloblastomas. We describe how they provide critical insights into the molecular and cellular events involved in the initiation and maintenance of brain tumors, and illustrate their use in preclinical drug testing. 相似文献
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Viré E Brenner C Deplus R Blanchon L Fraga M Didelot C Morey L Van Eynde A Bernard D Vanderwinden JM Bollen M Esteller M Di Croce L de Launoit Y Fuks F 《Nature》2006,439(7078):871-874
The establishment and maintenance of epigenetic gene silencing is fundamental to cell determination and function. The essential epigenetic systems involved in heritable repression of gene activity are the Polycomb group (PcG) proteins and the DNA methylation systems. Here we show that the corresponding silencing pathways are mechanistically linked. We find that the PcG protein EZH2 (Enhancer of Zeste homolog 2) interacts-within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)-with DNA methyltransferases (DNMTs) and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicate that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Furthermore, we show by bisulphite genomic sequencing that EZH2 is required for DNA methylation of EZH2-target promoters. Our results suggest that EZH2 serves as a recruitment platform for DNA methyltransferases, thus highlighting a previously unrecognized direct connection between two key epigenetic repression systems. 相似文献