Journal
CELL REPORTS
Volume 25, Issue 10, Pages 2729-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.11.029
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Funding
- European Union through the Seventh Framework Programme (FP7) under the project DESIRE [N602531]
- European Research Council (ERC) grant ChroNeuroRepair
- Health Research Council of New Zealand
- Cure Kids NZ
- German Research Foundation [CA 1205/2-1]
- Deutshcer Akademischer Austauschdienst of the German Research Council
- University of Otago
- Neurological Foundation of New Zealand
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The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development.
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