X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3.
Jia Hui Sun,Jiang Chen,Fernando Eduardo Ayala Valenzuela,Carolyn Brown,Diane Masser-Frye,Marilyn C. Jones,Leslie Patrón Romero,Berardo Rinaldi,Wenhui Laura Li,Qing Qing Li,Dan Wu,Bénédicte Gérard,Erin Thorpe,Allan Bayat,Yun Stone Shi +14 more
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TLDR
In this article, a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) was identified in a 1-year-old female patient with severe epilepsy and global developmental delay.Abstract:
The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.read more
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The p.Glu787Lys variant in the GRIA3 gene causes developmental and epileptic encephalopathy mimicking structural epilepsy in a female patient.
Anastasia Martinez-Esteve Melnikova,Jordi Pijuan,Javier Aparicio,Alia Ramirez,Anna Altisent-Huguet,Alba Vilanova-Adell,Alexis Arzimanoglou,Judith Armstrong,Francesc Palau,Janet Hoenicka,Victoria San Antonio-Arce +10 more
TL;DR: In this paper , a female pediatric patient with structural epilepsy carried a de novo missense variant in GRIA3 (c.2359G>A; p.Glu787Lys).
Journal ArticleDOI
Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome
Vardha Ismail,Linda G. Zachariassen,Annie Godwin,Mane Sahakian,Sian Ellard,Karen Stals,Emma L. Baple,Kate Tatton Brown,Nicola Foulds,Gabrielle Wheway,Matthew O. Parker,Signe M. Lyngby,Miriam Grønlund Pedersen,Julie Désir,Allan Bayat,Maria Musgaard,Matthew Guille,Anders S. Kristensen,Diana Baralle +18 more
TL;DR: In this article , the human phenotype associated with deleterious GRIA1 sequence variants was identified through international collaboration and detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression.
Journal ArticleDOI
Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant
Kohei Hamanaka,Keita Miyoshi,Jia-Hui Sun,Keisuke Hamada,Takao Komatsubara,Ken Saida,Naomi Tsuchida,Yuri Uchiyama,Atsushi Fujita,Takeshi Mizuguchi,Bénédicte Gérard,Allan Bayat,Berardo Rinaldi,Mitsuhiro Kato,Jun Tohyama,Kazuhiro Ogata,Yun Shi,Kuniaki Saito,Satoko Miyatake,Naomichi Matsumoto +19 more
TL;DR: Results suggest that p.Ala615Val has GOF effects, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype of GRIA3 -related NDDs.
Journal ArticleDOI
Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human
Shi-Xiao Peng,Jingwen Pei,Berardo Rinaldi,Jiang Chen,Yu‑Han Ge,Min Jia,Jun Wang,Andrée Delahaye-Duriez,Jia-Hui Sun,Yan-Yu Zang,Yong-Yun Shi,Jing Zhang,Xiang Gao,Donatella Milani,Xijia Xu,Nengyin Sheng,Bénédicte Gérard,Chen Zhang,Allan Bayat,Na Li,Jianke Yang,Yun Shi +21 more
TL;DR: This study identified two rare missense variants in X-linked GRIA3 from male patients who showed syndromes featuring aggressive outbursts and provided compelling evidence that dysfunction of AMPA receptor GluA3 promotes aggressive behavior.
Journal ArticleDOI
GluA3-containing AMPA receptors: From physiology to synaptic dysfunction in brain disorders.
TL;DR: In this article, the authors focused their attention on GluA3-containing AMPARs, addressing their functional role in synaptic transmission and synaptic plasticity and their involvement in a variety of brain disorders.
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