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

Am J Hum Genet. 2016 Dec 1;99(6):1359-1367. doi: 10.1016/j.ajhg.2016.10.006.

Chanshuai Han ¹, Reem Alkhater ², Tawfiq Froukh ³, Arakel G Minassian ⁴, Melissa Galati ¹, Rui Han Liu ¹, Maryam Fotouhi ¹, Julia Sommerfeld ⁵, Ayman J Alfrook ⁶, Christian Marshall ⁴, Susan Walker ⁴, Peter Bauer ⁵, Stephen W Scherer ⁷, Olaf Riess ⁵, Rebecca Buchert ⁵, Berge A Minassian ⁸, Peter S McPherson ⁹

Affiliations

1 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
2 Johns Hopkins Aramco Healthcare, Dhahran 34465, Saudi Arabia.
3 Department of Biotechnology and Genetic Engineering, Faculty of Science, Philadelphia University, Amman 11118, Jordan.
4 Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
5 Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany.
6 Private clinic, Amman 11118, Jordan.
7 Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada.
8 Program in Genetics and Genome Biology, Department of Pediatrics (Neurology), Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada.
9 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: [email protected].

PMID: 27866705 DOI: 10.1016/j.ajhg.2016.10.006

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.

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