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.

• Authors: P Joel Ross, Wen-Bo Zhang, Rebecca S F Mok, Kirill Zaslavsky, Eric Deneault, Lia D'Abate, Deivid C Rodrigues, Ryan K C Yuen, Muhammad Faheem, Marat Mufteev, Alina Piekna, Wei Wei, Peter Pasceri, Rebecca J Landa, Andras Nagy, Balazs Varga, Michael W Salter, Stephen W Scherer, James Ellis
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 87 Issue 2 Pg. 139-149 (01 15 2020) ISSN: 1873-2402 [Electronic] United States
• PMID: 31540669 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• PTCHD1 protein, human

Topics

• Autism Spectrum Disorder (genetics)
• Autistic Disorder (genetics)
• Humans
• Induced Pluripotent Stem Cells
• Male
• Membrane Proteins
• Neurons
• Synapses