\u8bb2\u5ea7\u5185\u5bb9\uff1aDiscovery of mutations in O-GlcNAc transferase leading to X-linked intellectual disability<\/p>\n
\u62a5\u544a\u4eba\uff1a Daan van Aalten \u6559\u6388\uff08\u82f1\u56fd\u9093\u8fea\u5927\u5b66\uff09<\/p>\n
\u4e3b \u6301 \u4eba\uff1a\u8881 \u51ef \u6559\u6388<\/p>\n
\u65f6\u00a0\u00a0\u00a0 \u95f4\uff1a2017\u5e7412\u670819\u65e5 \u4e0a\u534810:00<\/p>\n
\u5730\u00a0\u00a0\u00a0 \u70b9\uff1a\u4e2d\u5357\u5927\u5b66\u533b\u5b66\u9057\u4f20\u5b66\u7814\u7a76\u4e2d\u5fc3\u8001\u697c5\u697c\u5b66\u672f\u62a5\u544a\u5385<\/p>\n
van Aalten\u6559\u6388\u73b0\u4e3a\u82f1\u56fdDundee\u5927\u5b66\u751f\u547d\u79d1\u5b66\u9662\u6559\u6388\uff0c\u535a\u58eb\u751f\u5bfc\u5e08\u3002\u591a\u5e74\u6765\u81f4\u529b\u4e8eO-GlcNAc\u7cd6\u57fa\u5316\u5206\u5b50\u673a\u5236\u7684\u7814\u7a76\uff0c\u662fO-GlcNac\u7814\u7a76\u9886\u57df\u7684\u9876\u5c16\u4e13\u5bb6\uff0c\u5728Science\uff0cNature\uff0cNature Chemical Biology, Nature Structural Molecular Biology, PNAS, eLife\u7b49\u6742\u5fd7\u4e0a\u53d1\u8868170\u4f59\u7bc7\u9ad8\u6c34\u5e73\u7814\u7a76\u8bba\u6587\uff0c\u88ab\u5f15\u75289000\u4f59\u6b21\uff0c\u7bc7\u5747\u5f15\u752854\u6b21\uff0cH\u56e0\u5b50\u9ad8\u8fbe52\u3002\u4ed6\u5148\u540e\u83b7\u5f97EMBO long-term fellowship, Wellcome Trust Research Career Development Fellowship, \u548cWellcome Trust Senior Research Fellowship\u7b49\u7684\u8d44\u52a9\uff0c\u6240\u83b7\u7814\u7a76\u7ecf\u8d39\u7d2f\u8ba1\u8d85\u8fc73000\u4e07\u82f1\u9551\u3002\u5e76\u88ab\u6388\u4e88EMBO Young Investigator Award, Lister Institute for Preventive Medicine Research Prize, Royal Society of Chemistry\u2019s Dextra Laboratories Carbohydrate Award\u30022010\u5e74\uff0c\u88ab\u9009\u4e3aThe Royal Society of Edinburgh\u7684\u4f1a\u58eb\u30022017\u5e74\u53d7\u8058\u4e3a\u4e2d\u5357\u5927\u5b66\u6e58\u96c5\u533b\u9662\u5ba2\u5ea7\u6559\u6388\u3002<\/p>\n
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Abstract<\/u>\uff1aX-linked intellectual disability is a broad spectrum of monogenic disease covering over 800 genes. We have discovered mutations in O-GlcNAc transferase, leading to X-linked intellectual disability and general developmental delay.\u00a0Protein O-GlcNAcylation is a reversible posttranslational modification of Ser\/Thr on nucleocytoplasmic proteins in metazoa. This modification is essential for life at the single cell level and regulates a range of cellular processes such as metabolism, transcription, translation and signalling pathways. Defects in protein O-GlcNAcylation have been linked to diabetes, cancer and neurodegenerative disease. However, the link between O-GlcNAcylation of specific proteins and these processes\/diseases remains largely unexplored.\u00a0 Deletion of the O-GlcNAc transferase (OGT) or O-GlcNAc hydrolase (OGA) genes in invertebrate\/vertebrate models gives rise to lethality. Using the remarkable developmental phenotypes of the XLID patients and\u00a0O-GlcNAc deficient Drosophila<\/em> as a starting point, my lab is focused on discovering the O-GlcNAc proteins linked to these phenotypes, and the cellular processes involved, using a combination of chemical biology, structural biology, biochemistry and genetics. We have been the first to described the structures and mechanisms of the OGA and OGT enzymes. We have then exploited this detailed structural knowledge to design potent inhibitors, and applied these to study the effect of modulating cellular O-GlcNAc levels and the effects on specific signalling pathways. Currently we are developing novel tools for the enrichment and MS\/MS identification of O-GlcNAc proteins from Drosophila<\/em> embryos and are inducing hypo-O-GlcNAcylation and disease mutations\u00a0by means of CRISPR\/Cas9 gene editing technology and the delivery of specific OGT inhibitors to ultimately allow us to study the mechanisms behind individual O-GlcNAc sites.<\/p>\n <\/p>\n <\/p>\n","protected":false},"excerpt":{"rendered":"