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Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism

Pilorge, Marion; Fassier, Coralie; Le Corronc, Hervé; Potey, Anaïs; Bai, Jing; De Gois, S; Delaby, Elsa; Assouline, Brigitte; Guinchat, Vincent and Devillard, Francoise, et al. (2016) In Molecular Psychiatry 21. p.936-945
Abstract
Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity.

Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the

overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are

ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory

action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote

cortical interneuron migration and the generation of excitatory projection... (More)
Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity.

Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the

overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are

ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory

action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote

cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of

the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the

gene (GLRA2Δex8–9). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from

controls. In vitro functional analysis demonstrated that the GLRA2Δex8–9 protein failed to localize to the cell membrane, while the

R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo

missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression

and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild

type but not GLRA2Δex8–9 or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice

exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these

results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and

link altered glycinergic signaling to social and cognitive impairments. (Less)
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Contribution to journal
publication status
published
subject
keywords
Autism spectrum disorder (ASD), males, GLRA2, glycinergic signaling
in
Molecular Psychiatry
volume
21
pages
936 - 945
publisher
Nature Publishing Group
external identifiers
  • scopus:84941661770
  • wos:000378085600010
ISSN
1359-4184
DOI
10.1038/mp.2015.139
language
English
LU publication?
no
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d494ff23-d1e4-4e57-9a28-8d1e9f610b4e (old id 7985116)
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2016-02-15 11:25:17
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2017-11-05 03:04:54
@article{d494ff23-d1e4-4e57-9a28-8d1e9f610b4e,
  abstract     = {Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity.<br/><br>
Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the<br/><br>
overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are<br/><br>
ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory<br/><br>
action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote<br/><br>
cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of<br/><br>
the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the<br/><br>
gene (GLRA2Δex8–9). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from<br/><br>
controls. In vitro functional analysis demonstrated that the GLRA2Δex8–9 protein failed to localize to the cell membrane, while the<br/><br>
R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo<br/><br>
missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression<br/><br>
and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild<br/><br>
type but not GLRA2Δex8–9 or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice<br/><br>
exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these<br/><br>
results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and<br/><br>
link altered glycinergic signaling to social and cognitive impairments.},
  author       = {Pilorge, Marion and Fassier, Coralie and Le Corronc, Hervé and Potey, Anaïs and Bai, Jing and De Gois, S and Delaby, Elsa and Assouline, Brigitte and Guinchat, Vincent and Devillard, Francoise and Delorme, Richard and Nygren, Gudrun and Råstam, Maria and Meier, Jochen and Otani, Satoru and Cheval, Hélène and James, Victoria and Topf, Maya and Dear, Neil and Gillberg, Christopher and Leboyer, Marion and Giros, Bruno and Gautron, Sophie and Hazan, Jamilé and Harvey, Robert and Legendre, Pascal and Betancur, Catalina},
  issn         = {1359-4184},
  keyword      = {Autism spectrum disorder (ASD),males,GLRA2,glycinergic signaling},
  language     = {eng},
  pages        = {936--945},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Psychiatry},
  title        = {Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism},
  url          = {http://dx.doi.org/10.1038/mp.2015.139},
  volume       = {21},
  year         = {2016},
}