title: 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.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Chanshuai
authors.initials: C
authors.lastname: Han
authors.affiliation: Johns Hopkins Aramco Healthcare, Dhahran 34465, Saudi Arabia.
authors.forename: Reem
authors.initials: R
authors.lastname: Alkhater
authors.affiliation: Department of Biotechnology and Genetic Engineering, Faculty of Science, Philadelphia University, Amman 11118, Jordan.
authors.forename: Tawfiq
authors.initials: T
authors.lastname: Froukh
authors.affiliation: Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Arakel G
authors.initials: AG
authors.lastname: Minassian
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Galati
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Rui Han
authors.initials: RH
authors.lastname: Liu
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Fotouhi
authors.affiliation: Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Sommerfeld
authors.affiliation: Private clinic, Amman 11118, Jordan.
authors.forename: Ayman J
authors.initials: AJ
authors.lastname: Alfrook
authors.affiliation: Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Marshall
authors.affiliation: Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.affiliation: Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.affiliation: 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.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buchert
authors.affiliation: Program in Genetics and Genome Biology, Department of Pediatrics (Neurology), Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada.
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: peter.mcpherson@mcgill.ca.
authors.forename: Peter S
authors.initials: PS
authors.lastname: McPherson
mesh_terms: D000293:Adolescent; D000818:Animals; D001921:Brain / Q000473:pathology*; D002648:Child; D003241:Consanguinity; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008297:Male; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010375:Pedigree; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: C574860:DENND5A protein, human; D020662:Guanine Nucleotide Exchange Factors; D020691:rab GTP-Binding Proteins