Novel GRIA2 variant in a patient with atypical autism spectrum disorder and psychiatric symptoms: a case report

Cai, Qianyun; Zhou, Zhongjie; Luo, Rong; Yu, Tao; Li, Dengfeng; Yang, Fan; Yang, Zuozhen

doi:10.1186/s12887-022-03702-7

Cited by 4 publications

(1 citation statement)

References 19 publications

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“…Variants in human neurexins (NRXN1) and neuroligins (NLGN3) are associated with increased risk for autism (Supplementary Table 1), a neurodevelopmental condition characterized by altered social and communication behaviors, repetitive behaviors, and sensory processing/sensitivity 48,49 . Importantly, through our mechanistic exploration of the social feeding circuit and behavior, we uncovered novel roles for additional conserved autism-associated genes, including GRIA1,2,3(glr-1) [95][96][97] , GRIA2(glr-2) [95][96][97] , and GLRA2,GABRA3(avr-15) [98][99][100] (Supplementary Table 1) 101,102 . Rodent models for some of these genes also implicate them in social behaviors [103][104][105][106] .…”

Section: Discussionmentioning

confidence: 99%

Conserved autism-associated genes tune social feeding behavior inC. elegans

Cowen,

Reddy,

Chalasani

et al. 2023

Preprint

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Animal foraging is an essential and evolutionarily conserved behavior that occurs in social and solitary contexts, but the underlying molecular pathways are not well defined. We discover that conserved autism-associated genes (NRXN1(nrx-1),NLGN3(nlg-1),GRIA1,2,3(glr-1),GRIA2(glr-2), andGLRA2,GABRA3(avr-15))regulate aggregate feeding inC. elegans, a simple social behavior. NRX-1 functions in chemosensory neurons (ADL and ASH) independently of its postsynaptic partner NLG-1 to regulate social feeding. Glutamate from these neurons is also crucial for aggregate feeding, acting independently of NRX-1 and NLG-1. Compared to solitary counterparts, social animals show faster presynaptic release and more presynaptic release sites in ASH neurons, with only the latter requiringnrx-1. Disruption of these distinct signaling components additively converts behavior from social to solitary. Aggregation induced by circuit activation is also dependent onnrx-1. Collectively, we find that aggregate feeding is tuned by conserved autism-associated genes through complementary synaptic mechanisms, revealing molecular principles driving social feeding.TEASERConserved autism-associated genes mediate distinct molecular and circuit signaling components that cooperate to tuneC. eleganssocial feeding behavior.

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Section: Discussionmentioning

confidence: 99%

Conserved autism-associated genes tune social feeding behavior inC. elegans

Cowen,

Reddy,

Chalasani

et al. 2023

Preprint

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Conserved autism-associated genes tune social feeding behavior in C. elegans

Cowen,

Haskell,

Zoga

et al. 2024

Nat Commun

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Animal foraging is an essential and evolutionarily conserved behavior that occurs in social and solitary contexts, but the underlying molecular pathways are not well defined. We discover that conserved autism-associated genes ( NRXN1(nrx-1) , NLGN3(nlg-1) , GRIA1,2,3(glr-1) , GRIA2(glr-2) , and GLRA2,GABRA3(avr-15)) regulate aggregate feeding in C. elegans , a simple social behavior. NRX-1 functions in chemosensory neurons (ADL and ASH) independently of its postsynaptic partner NLG-1 to regulate social feeding. Glutamate from these neurons is also crucial for aggregate feeding, acting independently of NRX-1 and NLG-1. Compared to solitary counterparts, social animals show faster presynaptic release and more presynaptic release sites in ASH neurons, with only the latter requiring nrx-1 . Disruption of these distinct signaling components additively converts behavior from social to solitary. Collectively, we find that aggregate feeding is tuned by conserved autism-associated genes through complementary synaptic mechanisms, revealing molecular principles driving social feeding.

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Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes

Rinaldi,

Bayat,

Zachariassen

et al. 2023

Brain

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AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function (LoF) or gain-of-function (GoF) properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12), and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3-associated NDDs and distinct NDD phenotypes for LoF and GoF variants. GoF variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age one month), hypertonic, and more often had movement disorders, including hyperekplexia. Patients with LoF variants were older at the time of seizure onset (median age 16 months), hypotonic, and had sleeping disturbances. LoF and GoF variants were disease-causing in both sexes but affected males often carried de novo or hemizygous LoF variants inherited from healthy mothers, whereas all but one affected females had de novo heterozygous GoF variants.

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Novel GRIA2 variant in a patient with atypical autism spectrum disorder and psychiatric symptoms: a case report

Cited by 4 publications

References 19 publications

Conserved autism-associated genes tune social feeding behavior inC. elegans

Conserved autism-associated genes tune social feeding behavior inC. elegans

Conserved autism-associated genes tune social feeding behavior in C. elegans

Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes

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