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Series GSE143908 Query DataSets for GSE143908
Status Public on Jun 07, 2021
Title Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involving CHRNA7.
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Copy number variants at chromosome 15q13.3 contribute to liability for multiple intellectual and developmental disabilities (IDDs) including Autism Spectrum Disorder (ASD). Individuals with duplications of this interval, which includes the gene CHRNA7, have IDDs with variable penetrance. However, the basis of such differential affectation remains uncharacterized.Methods: Induced pluripotent stem cell (iPSC) models were generated from two first degree relatives with the same 15q13.3 duplication, a boy with distinct features of autism and emotional dysregulation (the affected proband, AP) and his clinically unaffected mother (the UM). These models were compared to unrelated control subjects lacking this duplication (UC, male and female). iPSC-derived neural progenitors and cortical neuroids consisting of cortical excitatory and inhibitory neurons were used to model potential contributors to neuropsychiatric impairment. Results: The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or in unrelated male and female controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress in neural progenitors. Both the AP’s neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also specifically dysregulated in the AP, including altered expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and WNT signaling. By contrast with these AP-specific phenotypes, both the AP- and UM-derived neurons exhibited shared alterations of neuronal function, including elevated cholinergic activity consistent with increased homomeric CHRNA7 channel activity.Conclusion: Together, these data define both affectation-specific phenotypes seen only in the AP, as well as abnormalities observed in both individuals with CHRNA7 duplication, the AP and UM, but not in UC-derived neurons. This is, to our knowledge, the first study to use a human stem cell-based platform to study the basis of variable affectation in cases of 15q13.3 duplication at the cellular, molecular, and functional levels. This work suggests potential approaches for suppressing abnormal neurodevelopment or physiology that may contribute to severity of affectation in this proband. Some of these AP-specific neurodevelopmental anomalies, or the functional anomalies observed in both 15q13.3 duplication carriers (the AP and UM), could also contribute to the differential phenotypic penetrance seen in other individuals with 15q13.3 duplication.
Overall design iPSC's were generated from patients with 15q13.3 duplication involving two first degree relatives (Affected Proband (AP), Unaffected Mother (UM)), with and without affectation. The Neural Progenitor Cells were generated from the iPSCs, and they are further matured for 15 days as a cortical neuroids. This study also includes two unrelated male (UC-M) and female (UC-F) control samples. Four independent biological experiments were performed and RNA was isolated from cortical neuroids after 15 days of differentiation. A batch correction was used to identify genes that were reproducibly differentially expressed genes (DEGs) across comparisons of paired mutant versus control samples.
Contributor(s) Meganathan K, Prakasam R, Baldridge D, Gontarz P, Zhang B, Urano F, Bonni A, Huettner JE, Constantino JN, Kroll KL
Citation(s) 34320968
Submission date Jan 18, 2020
Last update date Sep 07, 2021
Contact name Kristen L Kroll
Organization name Washington University School of Medicine
Department Developmental Biology
Lab Kristen Kroll
Street address 320 McDonnell Sciences/660 S. Euclid Ave.
City Saint Louis
State/province MO
ZIP/Postal code 63110
Country USA
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (16)
GSM4276562 UC_F_a
GSM4276563 UC_F_b
GSM4276564 UC_F_c
BioProject PRJNA602086
SRA SRP242691

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Supplementary file Size Download File type/resource
GSE143908_fCount.txt.gz 1.0 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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