Journal
BIOLOGICAL PSYCHIATRY
Volume 87, Issue 2, Pages 139-149Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2019.07.014
Keywords
Autism spectrum disorder; Excitatory synapses; Genetics; Induced pluripotent stem cells; Long non-coding RNA; Neurons
Categories
Funding
- National Institutes of Health [R33 MH087908, R01 MH059630]
- Canadian Institutes of Health Research (CIHR) [EPS-129129, MOP-102649, MOP-133423]
- Genome Canada
- Autism Speaks MSSNG Project
- Canadian Institute for Advanced Research
- Ontario Brain Institute
- Simons Foundation for Autism Research [569293]
- Ontario Stem Cell Initiative Fellowship
- Ontario Ministry of Research and Innovation Fellowship
- CIHR Banting Postdoctoral Fellowship
- CIHR Vanier Scholarship
- International Rett Syndrome Foundation Fellowship
- CIHR Postdoctoral Fellowship
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BACKGROUND: The Xp22.11 locus that encompasses PTCHD1, DDX53, and the long noncoding RNA PTCHD1-AS is frequently disrupted in male subjects with autism spectrum disorder (ASD), but the functional consequences of these genetic risk factors for ASD are unknown. METHODS: To evaluate the functional consequences of PTCHD1 locus deletions, we generated induced pluripotent stem cells (iPSCs) from unaffected control subjects and 3 subjects with ASD with microdeletions affecting PTCHD1-AS/PTCHD1, PTCHD1-AS/DDX53, or PTCHD1-AS alone. Function of iPSC-derived cortical neurons was assessed using molecular approaches and electrophysiology. We also compiled novel and known genetic variants of the PTCHD1 locus to explore the roles of PTCHD1 and PTCHD1-AS in genetic risk for ASD and other neurodevelopmental disorders. Finally, genome editing was used to explore the functional consequences of deleting a single conserved exon of PTCHD1-AS. RESULTS: iPSC-derived neurons from subjects with ASD exhibited reduced miniature excitatory postsynaptic current frequency and N-methyl-D-aspartate receptor hypofunction. We found that 35 ASD-associated deletions mapping to the PTCHD1 locus disrupted exons of PTCHD1-AS. We also found a novel ASD-associated deletion of PTCHD1-AS exon 3 and showed that exon 3 loss altered PTCHD1-AS splicing without affecting expression of the neighboring PTCHD1 coding gene. Finally, targeted disruption of PTCHD1-AS exon 3 recapitulated diminished miniature excitatory postsynaptic current frequency, supporting a role for the long noncoding RNA in the etiology of ASD. CONCLUSIONS: 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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