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Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A.

ABSTRACT: 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-function mutations 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 in neuronal 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.

SUBMITTER: Han C

PROVIDER: S-EPMC5142110 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A.

Han Chanshuai C Alkhater Reem R Froukh Tawfiq T Minassian Arakel G AG Galati Melissa M Liu Rui Han RH Fotouhi Maryam M Sommerfeld Julia J Alfrook Ayman J AJ Marshall Christian C Walker Susan S Bauer Peter P Scherer Stephen W SW Riess Olaf O Buchert Rebecca R Minassian Berge A BA McPherson Peter S PS

American journal of human genetics 20161117 6

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-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to m ...[more]

PMID: 27866705

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Dataset Information

Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A.

Publications

Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A.

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