TY - JOUR
T1 - Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A
AU - Han, Chanshuai
AU - Alkhater, Reem
AU - Froukh, Tawfiq
AU - Minassian, Arakel G.
AU - Galati, Melissa
AU - Liu, Rui Han
AU - Fotouhi, Maryam
AU - Sommerfeld, Julia
AU - Alfrook, Ayman J.
AU - Marshall, Christian
AU - Walker, Susan
AU - Bauer, Peter
AU - Scherer, Stephen W.
AU - Riess, Olaf
AU - Buchert, Rebecca
AU - Minassian, Berge A.
AU - McPherson, Peter S.
N1 - Publisher Copyright:
© 2016 American Society of Human Genetics
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2016.10.006
DO - 10.1016/j.ajhg.2016.10.006
M3 - Article
C2 - 27866705
AN - SCOPUS:85003827400
SN - 0002-9297
VL - 99
SP - 1359
EP - 1367
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -