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

Chanshuai Han, Reem Alkhater, Tawfiq Froukh, Arakel G. Minassian, Melissa Galati, Rui Han Liu, Maryam Fotouhi, Julia Sommerfeld, Ayman J. Alfrook, Christian Marshall, Susan Walker, Peter Bauer, Stephen W. Scherer, Olaf Riess, Rebecca Buchert, Berge A. Minassian, Peter S. McPherson

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1359-1367
Number of pages9
JournalAmerican Journal of Human Genetics
Volume99
Issue number6
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Han, C., Alkhater, R., Froukh, T., Minassian, A. G., Galati, M., Liu, R. H., Fotouhi, M., Sommerfeld, J., Alfrook, A. J., Marshall, C., Walker, S., Bauer, P., Scherer, S. W., Riess, O., Buchert, R., Minassian, B. A., & McPherson, P. S. (2016). Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A. American Journal of Human Genetics, 99(6), 1359-1367. https://doi.org/10.1016/j.ajhg.2016.10.006