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

Autor: Chapman G; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; School of Biosciences, The Sir Martin Evans Building, Museum Ave, Cardiff University, Cardiff, United Kingdom., Alsaqati M; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, United Kingdom., Lunn S; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; School of Biosciences, The Sir Martin Evans Building, Museum Ave, Cardiff University, Cardiff, United Kingdom., Singh T; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; School of Biosciences, The Sir Martin Evans Building, Museum Ave, Cardiff University, Cardiff, United Kingdom., Linden SC; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, United Kingdom.; Care and Public Health Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands., Linden DEJ; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, United Kingdom.; School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands., van den Bree MBM; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, United Kingdom., Ziller M; MaxPlanck Institute for Psychiatry, Munich, Germany., Owen MJ; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, United Kingdom., Hall J; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; Division of Psychological Medicine and Clinical Neurosciences (DPMCN), School of Medicine, Cardiff University, Cardiff, United Kingdom., Harwood AJ; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.; School of Biosciences, The Sir Martin Evans Building, Museum Ave, Cardiff University, Cardiff, United Kingdom., Syed YA; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom. syedy@cardiff.ac.uk.; School of Biosciences, The Sir Martin Evans Building, Museum Ave, Cardiff University, Cardiff, United Kingdom. syedy@cardiff.ac.uk.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Feb; Vol. 27 (2), pp. 819-830. Date of Electronic Publication: 2021 Jun 10.
DOI: 10.1038/s41380-021-01182-2
Abstrakt: 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 Ca 2+ 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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