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

• Published in: American journal of human genetics Vol. 99; no. 6; pp. 1359 - 1367
• Main Authors: Han, Chanshuai, Alkhater, Reem, Froukh, Tawfiq, Minassian, Arakel G., Galati, Melissa, Liu, Rui Han, Fotouhi, Maryam, Sommerfeld, Julia, Alfrook, Ayman J., Marshall, Christian, Walker, Susan, Bauer, Peter, Scherer, Stephen W., Riess, Olaf, Buchert, Rebecca, Minassian, Berge A., McPherson, Peter S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2016; Cell Press; Elsevier
• Subjects: Adolescent; Animals; Brain; Brain - pathology; Child; Consanguinity; Convulsions & seizures; Epilepsy; Epilepsy - genetics; Female; Humans; Male; Mutation; Neurons; Neurons - metabolism; PC12 Cells; Pedigree; Proteins; rab GTP-Binding Proteins - genetics; Rats
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2016.10.006

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.