@article{3907ef43ddae42619f571bc693767f8e,
title = "Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS",
abstract = "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.",
keywords = "Autism spectrum disorder, Excitatory synapses, Genetics, Induced pluripotent stem cells, Long noncoding RNA, Neurons",
author = "Ross, {P. Joel} and Zhang, {Wen Bo} and Mok, {Rebecca S.F.} and Kirill Zaslavsky and Eric Deneault and Lia D'Abate and Rodrigues, {Deivid C.} and Yuen, {Ryan K.C.} and Muhammad Faheem and Marat Mufteev and Alina Piekna and Wei Wei and Peter Pasceri and Landa, {Rebecca J.} and Andras Nagy and Balazs Varga and Salter, {Michael W.} and Scherer, {Stephen W.} and James Ellis",
note = "Funding Information: This study was supported by the National Institutes of Health (Grant No. R33 MH087908 [to JE and SWS] and Grant No. R01 MH059630 [to RJL]), Canadian Institutes of Health Research (CIHR) (Grant No. EPS-129129 [to JE and AN] and Grant Nos. MOP-102649 and MOP-133423 [to JE and MWS]), Genome Canada (to SWS), Autism Speaks MSSNG Project, Canadian Institute for Advanced Research, Ontario Brain Institute (to JE and SWS), Simons Foundation for Autism Research (Grant No. 569293 [to SWS and MWS]), Ontario Stem Cell Initiative Fellowship (to PJR), Ontario Ministry of Research and Innovation Fellowship (to PJR), CIHR Banting Postdoctoral Fellowship (to ED), CIHR Vanier Scholarship (to KZ), International Rett Syndrome Foundation Fellowship (to DCR), and CIHR Postdoctoral Fellowship (to RKCY). SWS is the GlaxoSmithKline-CIHR Endowed Chair in Genome Sciences at The Hospital for Sick Children. MWS is the Northbridge Chair in Paediatric Research at the Hospital for Sick Children. Author responsibilities were as follows: conceptualization—JE, SWS, PJR, MWS, and W-BZ; methodology—PJR, JE, W-BZ, MWS, RSFM, KZ, ED, BV, AN, DCR, LD, and SWS; formal analysis—PJR, JE, W-BZ, MWS, KZ, RSFM, ED, LD, MF, MM, and RKCY; investigation—PJR, W-BZ, RSFM, KZ, ED, LD, DCR, AP, WW, PP, and RKCY; resources—RL; writing of original manuscript draft—PJR, JE, W-BZ, and KZ; review and editing of final manuscript—PJR, JE, W-BZ, MWS, SWS, KZ, ED, RSFM, LD, DCR, and PP; visualization—PJR, W-BZ, KZ, LD, ED, MM, and MF; supervision—JE, SWS, and MWS. We thank Dr. John Vincent for helpful discussions; Zhanna Konovalova, Tadeo Thompson, Attey Rostami, and Janice Hicks for technical support; Dr. Andrea Vaags for preliminary copy number variation analyses; and Drs. Wendy Roberts, Rosanna Weksberg, Brian Chung, and Melissa Carter for obtaining skin biopsy specimens. We also thank the participants and their family members for their contributions to this study. SWS is on the Scientific Advisory Committees of Population Bio and Deep Genomics, and the intellectual property from aspects of his research performed at the Hospital for Sick Children is licensed to Athena Diagnostics and Lineagen and co-held with Population Bio. These relationships did not influence data interpretation or presentation during this study, but are being disclosed for potential future considerations. The other authors report no relevant biomedical financial interests or potential conflicts of interest. Funding Information: This study was supported by the National Institutes of Health (Grant No. R33 MH087908 [to JE and SWS] and Grant No. R01 MH059630 [to RJL]), Canadian Institutes of Health Research (CIHR) (Grant No. EPS-129129 [to JE and AN] and Grant Nos. MOP-102649 and MOP-133423 [to JE and MWS]), Genome Canada (to SWS), Autism Speaks MSSNG Project , Canadian Institute for Advanced Research , Ontario Brain Institute (to JE and SWS), Simons Foundation for Autism Research (Grant No. 569293 [to SWS and MWS]), Ontario Stem Cell Initiative Fellowship (to PJR), Ontario Ministry of Research and Innovation Fellowship (to PJR), CIHR Banting Postdoctoral Fellowship (to ED), CIHR Vanier Scholarship (to KZ), International Rett Syndrome Foundation Fellowship (to DCR), and CIHR Postdoctoral Fellowship (to RKCY). SWS is the GlaxoSmithKline-CIHR Endowed Chair in Genome Sciences at The Hospital for Sick Children. MWS is the Northbridge Chair in Paediatric Research at the Hospital for Sick Children. Publisher Copyright: {\textcopyright} 2019 Society of Biological Psychiatry",
year = "2020",
month = jan,
day = "15",
doi = "10.1016/j.biopsych.2019.07.014",
language = "English (US)",
volume = "87",
pages = "139--149",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "2",
}