A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration
Adam C. O’Neill,
Christina Kyrousi,
Johannes Klaus,
Richard J. Leventer,
Edwin P. Kirk,
Andrew Fry,
Daniela T. Pilz,
Tim Morgan,
Zandra A. Jenkins,
Micha Drukker,
Samuel F. Berkovic,
Ingrid E. Scheffer,
Renzo Guerrini,
David M. Markie,
Magdalena Götz,
Silvia Cappello,
Stephen P. Robertson
Affiliations
Adam C. O’Neill
Department of Women’s and Children’s Health, University of Otago, Dunedin, New Zealand; Institute of Stem Cell Research, Helmholtz Center, Munich, Germany; Physiological Genomics, Biomedical Center Ludwig-Maximilians-Universitaet, Munich, Germany
Christina Kyrousi
Max Planck Institute of Psychiatry, Munich, Germany
Johannes Klaus
Max Planck Institute of Psychiatry, Munich, Germany
Richard J. Leventer
Department of Neurology, Murdoch Children’s Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
Edwin P. Kirk
Sydney Children’s Hospital, University of New South Wales, Randwick, NSW, Australia; New South Wales Health Pathology, Randwick, NSW, Australia
Andrew Fry
Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK
Daniela T. Pilz
West of Scotland Genetics Service, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK
Tim Morgan
Department of Women’s and Children’s Health, University of Otago, Dunedin, New Zealand
Zandra A. Jenkins
Department of Women’s and Children’s Health, University of Otago, Dunedin, New Zealand
Micha Drukker
Institute of Stem Cell Research, Helmholtz Center, Munich, Germany
Samuel F. Berkovic
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia
Ingrid E. Scheffer
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia
Renzo Guerrini
Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer-University of Florence, Florence, Italy
David M. Markie
Department of Pathology, University of Otago, Dunedin, New Zealand
Magdalena Götz
Institute of Stem Cell Research, Helmholtz Center, Munich, Germany; Physiological Genomics, Biomedical Center Ludwig-Maximilians-Universitaet, Munich, Germany; Excellence Cluster of Systems Neurology (SYNERGY), 82152 Planegg/Martinsried, Germany
Silvia Cappello
Max Planck Institute of Psychiatry, Munich, Germany; Corresponding author
Stephen P. Robertson
Department of Women’s and Children’s Health, University of Otago, Dunedin, New Zealand; Corresponding author
Summary: 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. : O’Neill et al. show that variants in patients with PH are enriched within genes that define basal radial glia transcriptomic signatures and provide mechanistic evidence that a primate-specific isoform of one gene, mutated in a patient with PH, regulates neurogenesis. Keywords: cortical development, evolution, periventricular heterotopia, PLEKHG6, MyoGEF, RhoA
