Sammanfattning
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.
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.
| Originalspråk | engelska |
|---|---|
| Sidor (från-till) | 936-945 |
| Tidskrift | Molecular Psychiatry |
| Volym | 21 |
| DOI | |
| Status | Published - 2016 |
| Externt publicerad | Ja |
Ämnesklassifikation (UKÄ)
- Neurovetenskaper
- Medicinsk genetik