Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS

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 Landa, Andras Nagy, Balazs Varga, Michael W. Salter, Stephen W. Scherer, James Ellis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalBiological psychiatry
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Autistic Disorder
Neurons
Induced Pluripotent Stem Cells
Exons
Long Noncoding RNA
Excitatory Postsynaptic Potentials
Autism Spectrum Disorder
Neurophysiology
Electrophysiology
N-Methyl-D-Aspartate Receptors
Synapses

Keywords

  • Autism spectrum disorder
  • Excitatory synapses
  • Genetics
  • Induced pluripotent stem cells
  • Long noncoding RNA
  • Neurons

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Ross, P. J., Zhang, W. B., Mok, R. S. F., Zaslavsky, K., Deneault, E., D'Abate, L., ... Ellis, J. (Accepted/In press). Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS. Biological psychiatry. https://doi.org/10.1016/j.biopsych.2019.07.014

Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS. / Ross, P. Joel; Zhang, Wen Bo; Mok, Rebecca S.F.; Zaslavsky, Kirill; Deneault, Eric; D'Abate, Lia; Rodrigues, Deivid C.; Yuen, Ryan K.C.; Faheem, Muhammad; Mufteev, Marat; Piekna, Alina; Wei, Wei; Pasceri, Peter; Landa, Rebecca; Nagy, Andras; Varga, Balazs; Salter, Michael W.; Scherer, Stephen W.; Ellis, James.

In: Biological psychiatry, 01.01.2019.

Research output: Contribution to journalArticle

Ross, PJ, Zhang, WB, Mok, RSF, Zaslavsky, K, Deneault, E, D'Abate, L, Rodrigues, DC, Yuen, RKC, Faheem, M, Mufteev, M, Piekna, A, Wei, W, Pasceri, P, Landa, R, Nagy, A, Varga, B, Salter, MW, Scherer, SW & Ellis, J 2019, 'Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS', Biological psychiatry. https://doi.org/10.1016/j.biopsych.2019.07.014
Ross, P. Joel ; Zhang, Wen Bo ; Mok, Rebecca S.F. ; Zaslavsky, Kirill ; Deneault, Eric ; D'Abate, Lia ; Rodrigues, Deivid C. ; Yuen, Ryan K.C. ; Faheem, Muhammad ; Mufteev, Marat ; Piekna, Alina ; Wei, Wei ; Pasceri, Peter ; Landa, Rebecca ; Nagy, Andras ; Varga, Balazs ; Salter, Michael W. ; Scherer, Stephen W. ; Ellis, James. / Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS. In: Biological psychiatry. 2019.
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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.",
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AU - Ross, P. Joel

AU - Zhang, Wen Bo

AU - Mok, Rebecca S.F.

AU - Zaslavsky, Kirill

AU - Deneault, Eric

AU - D'Abate, Lia

AU - Rodrigues, Deivid C.

AU - Yuen, Ryan K.C.

AU - Faheem, Muhammad

AU - Mufteev, Marat

AU - Piekna, Alina

AU - Wei, Wei

AU - Pasceri, Peter

AU - Landa, Rebecca

AU - Nagy, Andras

AU - Varga, Balazs

AU - Salter, Michael W.

AU - Scherer, Stephen W.

AU - Ellis, James

PY - 2019/1/1

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N2 - 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.

AB - 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.

KW - Autism spectrum disorder

KW - Excitatory synapses

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KW - Induced pluripotent stem cells

KW - Long noncoding RNA

KW - Neurons

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