期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 99, 期 6, 页码 1359-1367出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2016.10.006
关键词
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资金
- Canadian Institutes for Health Research [MOP-62684]
- German Academic Exchange Service as part of the German-Arab Transformation Program Line4 [57166498]
- Ontario Brain Institute and Genome Canada
- fellowship from Fonds de Recherche du Quebec - Sante [Dossier-30199, Dossier-33963]
Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-functionmutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations inneuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.
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