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Human Pluripotent stem cells: Normal diploid line vs lines with deletions of Chr7

ABSTRACT: Mapping deletions of Chr7 in human iPSC and ESCs derived from patients cells through reprogramming or chromosome engineering

ORGANISM(S): Homo sapiens

PROVIDER: GSE65386 | GEO | 2015/02/16

SECONDARY ACCESSION(S): PRJNA273863

REPOSITORIES: GEO

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Human Pluripotent stem cells: Normal diploid line vs lines with deletions of Chr7

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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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