Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involving CHRNA7.
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ABSTRACT:
PROVIDER: PRJNA602086 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10913263.fastq.gz | Fastqsanger.gz | |||
| SRR10913264.fastq.gz | Fastqsanger.gz | |||
| SRR10913265.fastq.gz | Fastqsanger.gz | |||
| SRR10913266.fastq.gz | Fastqsanger.gz | |||
| SRR10913267.fastq.gz | Fastqsanger.gz |
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Project description: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.
2021-06-07 | GSE143908 | GEO
Project description:BackgroundCopy number variants (CNVs) linked to genes involved in nervous system development or function are often associated with neuropsychiatric disease. While CNVs involving deletions generally cause severe and highly penetrant patient phenotypes, CNVs leading to duplications tend instead to exhibit widely variable and less penetrant phenotypic expressivity among affected individuals. CNVs located on chromosome 15q13.3 affecting the alpha-7 nicotinic acetylcholine receptor subunit (CHRNA7) gene contribute to multiple neuropsychiatric disorders with highly variable penetrance. However, the basis of such differential penetrance remains uncharacterized. Here, we generated induced pluripotent stem cell (iPSC) models from first-degree relatives with a 15q13.3 duplication and analyzed their cellular phenotypes to uncover a basis for the dissimilar phenotypic expressivity.ResultsThe first-degree relatives studied included a boy with autism and emotional dysregulation (the affected proband-AP) and his clinically unaffected mother (UM), with comparison to unrelated control models lacking this duplication. Potential contributors to neuropsychiatric impairment were modeled in iPSC-derived cortical excitatory and inhibitory neurons. The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or unrelated controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress. Both the neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also dysregulated in the AP, including reduced expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and Wnt, axonal guidance, and GABA receptor signaling. The UM model instead exhibited upregulated expression of genes in many of these same pathways, suggesting that molecular compensation could have contributed to the lack of neurodevelopmental phenotypes in this model. However, both AP- and UM-derived neurons exhibited shared alterations of neuronal function, including increased action potential firing and elevated cholinergic activity, consistent with increased homomeric CHRNA7 channel activity.ConclusionsThese data define both diagnosis-associated cellular phenotypes and shared functional anomalies related to CHRNA7 duplication that may contribute to variable phenotypic penetrance in individuals with 15q13.3 duplication. The capacity for pharmacological agents to rescue some neurodevelopmental anomalies associated with diagnosis suggests avenues for intervention for carriers of this duplication and other CNVs that cause related disorders.
| S-EPMC8317352 | biostudies-literature
Project description:Copy number variants have been associated with intellectual disability, multiple congenital anomalies and craniofacial disorders. It has been reported that microduplication of 15q13.3 is associated with autism, cognitive impairment, seizures, and attention-deficit hyperactivity disorder. Here, the author identified microduplications in the 15q13.3 region in 4 cases from 3 Chinese families using chromosomal microarray analysis-single nucleotide polymorphism array (CMA-SNP). These 4 cases include 2 fetuses from 2 unrelated families and a father and a daughter from a third family. The identified microduplications of 15q13.3 are approximately 400 kb in size, encompassing just 1 gene, cholinergic receptor, neuronal nicotinic, alpha polypeptide 7 (CHRNA7). Three-fourths of the probands exhibit oral clefts, which has not been previously reported in cases with this duplication genotype. Therefore, in this study, the author describes for the first time the common feature of oral clefts in patients carrying a microduplication of 15q13.3 encompassing the CHRNA7 gene, which sheds light on the correlation between CHRNA7 and cleft palate.
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Project description:Tandem duplication of carbapenemase genes amplifies the gene copy number and enhances carbapenem resistance. These amplifications are often heterogenous, transient, locate in plasmids, which often also contribute to heteroresistance. The duplication is especially important for low-hydrolysis activity enzymes, which is often overlooked or even under controversy. Here we reported an intrinsic oxacillinase duplication mediated by two neighbor ISAba1inserted in the same orientation. The duplication is relatively stable, located in chromosome, and the duplication times is up to twenty-five, much larger than previous reports. We provided genomic, transcriptomic, and proteomic evidence that the duplication resulted oxacillinase overproduction and thus contribute to carbapenem resistance. No other possible carbapenem resistance related changes (point mutations of oxaAb, disturbed expression of porin protein and efflux pump) were found during the duplication process. Furthermore, introducing oxaAb flanked by two ISAba1 to A. baumannii via plasmids, mimicked the in vivo duplication process under carbapenem stress. Taken together, ISAba1 mediated duplication of low activity intrinsic antibiotic hydrolysis enzymes could lead to antibiotic resistance for advanced-generation antibiotics.
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Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71229 | GEO
Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71234 | GEO
Project description:MECP2 duplication syndrome, a childhood neurological disorder characterized by autism, intellectual disability, motor dysfunction, anxiety and epilepsy, is caused by a duplication on chromosome Xq28 spanning the MECP2 gene that results in doubling of MeCP2 levels. MECP2 overexpression in mice causes neurobehavioral and electroencephalographic defects similar to those of human patients, but the gross anatomy of the brain remains unaffected. We hypothesized that MECP2 duplication syndrome would be reversible and tested two methods to restore MeCP2 levels to normal: conditional genetic recombination and antisense oligonucleotide therapy. Both approaches rescued molecular, physiological and behavioral features of adult symptomatic mice. Antisense therapy also restored normal MeCP2 levels in lymphoblastoid cells from MECP2 duplication patients, in a dose-dependent manner. Our data indicate that antisense oligonucleotides could provide a viable therapeutic approach for human MECP2 duplication syndrome as well as other disorders involving copy number gains.
2015-11-27 | GSE71233 | GEO