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 language | English (US) |
|---|---|
| Journal | Biological psychiatry |
| DOIs | |
| State | Accepted/In press - Jan 1 2019 |
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Keywords
- Autism spectrum disorder
- Excitatory synapses
- Genetics
- Induced pluripotent stem cells
- Long noncoding RNA
- Neurons
ASJC Scopus subject areas
- Biological Psychiatry
Cite this
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 journal › Article
}
TY - JOUR
T1 - Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS
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
Y1 - 2019/1/1
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
KW - Genetics
KW - Induced pluripotent stem cells
KW - Long noncoding RNA
KW - Neurons
UR - http://www.scopus.com/inward/record.url?scp=85072193504&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072193504&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2019.07.014
DO - 10.1016/j.biopsych.2019.07.014
M3 - Article
C2 - 31540669
AN - SCOPUS:85072193504
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
ER -