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Autism-associated deletions of the lncRNA PTCHD1-AS result in synaptic dysfunction in human neurons

ABSTRACT: The long non-coding (lnc) RNA PTCHD1-AS is frequently disrupted in males with autism spectrum disorder (ASD), but its role in neuron function is unknown. We generated induced pluripotent stem (iPS) cells from two ASD subjects with PTCHD1 locus microdeletions, and produced neurons that exhibited reduced miniature excitatory post-synaptic current (mEPSC) frequency and NMDA receptor hypofunction. Mutation of the lncRNA PTCHD1-AS had no impact on expression of the divergently transcribed neighboring PTCHD1 gene in cis, but 14 genes were differentially expressed. Alternative splicing patterns of the nuclear lncRNA were affected by exon 3 loss, and its importance was reinforced by discovery of a novel ASD-associated exon 3 deletion. Finally, genome editing of exon 3 in iPS cells recapitulated diminished mEPSC frequency in neurons. Our findings directly implicate PTCHD1-AS in excitatory synapse function, and reveal the first association of lncRNA deletion with neuronal under-connectivity in ASD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81624 | GEO | 2019/05/18

REPOSITORIES: GEO

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Synaptic dysfunction in human neurons with Autism associated deletions in PTCHD1-AS

Project description:The Xp22.11 locus that encompasses PTCHD1, DDX53, and the long noncoding RNA (lncRNA) PTCHD1-AS is frequently disrupted in males with autism spectrum disorder (ASD), but the functional consequences of these genetic risk factors for ASD are unknown. : iPSC-derived neurons from the ASD subjects exhibited reduced miniature excitatory post-synaptic current (mEPSC) frequency and NMDA receptor hypofunction. We found that 35 ASD-associated deletions mapping to the PTCHD1 locus disrupt exons of PTCHD1-AS. We also report a novel ASD-associated deletion of PTCHD1-AS exon 3, and we show exon 3 loss alters PTCHD1-AS splicing without affecting expression of the neighboring PTCHD1 coding gene. Finally, targeted disruption of PTCHD1-AS exon 3 recapitulated diminished mEPSC frequency, supporting a role for the lncRNA in the etiology of ASD. Our genetic findings provide strong evidence that PTCHD1-AS deletions are risk factors for ASD, and human iPSC-derived neurons implicate these deletions in the neurophysiology of excitatory synapses and in ASD-associated synaptic impairment.

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Copy number variation data from iPS cells with PTCHD1-AS deletions

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Synaptic dysfunction in human neurons with Autism associated deletions in PTCHD1-AS

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A CRISPR-engineered Isogenic Model Reveals Altered Neuronal Phenotypes of the 22q11.2 A-B Syndromic Deletion

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