Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome

ABSTRACT: Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Cav1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca2+) signaling and activity-dependent gene expression and show abnormalities in differentiation. Neurons from individuals with Timothy syndrome show increased expression of markers of the upper cortical layer and decreased expression of callosal projection markers. In addition, the mutation that causes Timothy syndrome leads to an increase in the production of neurons that synthesize norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase and atypical L-type–channel blocker. These findings provide strong evidence that Cav1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome. Total RNA was isolated from control and TS cells: fibroblasts, iPSCs, neurospheres (at day 7 in suspension), neurons at rest (day 45 of differentiation) and neurons kept in 67mM KCl for 9h. For sample titles, D1,D2 and D3 represent independent differentiation experiments. The number after - represents the iPSC cell line number. GSE25542_non-normalized.txt.gz contains data for 5 outliers.

ORGANISM(S): Homo sapiens

SUBMITTER: Irina Voineagu

PROVIDER: E-GEOD-25542 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome

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