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Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome

Chapman, Gareth, Alsaqati, Mouhamed, Lunn, Sharna, Singh, Tanya, Linden, Stephanie C. ORCID:, Linden, David E.J. ORCID:, van den Bree, Marianne B. V. ORCID:, Ziller, Mike, Owen, Michael J. ORCID:, Hall, Jeremy ORCID:, Harwood, Adrian J. ORCID: and Syed, Yasir Ahmed ORCID: 2022. Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome. Molecular Psychiatry 27 , pp. 819-830. 10.1038/s41380-021-01182-2

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Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Springer Nature
ISSN: 1359-4184
Date of First Compliant Deposit: 2 June 2021
Date of Acceptance: 27 May 2021
Last Modified: 11 Jun 2024 10:07

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