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ResearchIn-Press PreviewDevelopmentNeuroscience
Open Access | 10.1172/JCI153097
1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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Ferreira, S.
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
Find articles by Hayashi, K. in: JCI | PubMed | Google Scholar
1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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Altersitz, C.
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
Find articles by Rosello, M. in: JCI | PubMed | Google Scholar
1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
Find articles by Dang, J. in: JCI | PubMed | Google Scholar
1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
Find articles by Henry, O. in: JCI | PubMed | Google Scholar
1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
Find articles by Roux, C. in: JCI | PubMed | Google Scholar
1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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Bellesme, C.
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
Find articles by Freri, E. in: JCI | PubMed | Google Scholar
1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
Find articles by Parrini, E. in: JCI | PubMed | Google Scholar
1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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Guerrini, R.
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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Del Bene, F.
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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Nakajima, K.
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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Bahi-Buisson, N.
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1Team Genetics and Development of the Cerebral Cortex, Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, Paris, France
2Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
3Development and function of the vertebrate visual system, Institut de la Vision, Paris, France
4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
5Pediatric Radiology, Necker Enfants Malades University Hospital, Université de Paris, Paris, France
6Pediatric Neurology, Bicêtre University Hospital, Université Paris Saclay, Kremlin-Bicêtre, France
7Pediatric Neurology, Fondazione Istituto Neurologico, Milan, Italy
8Department of Clinical Genetics, Guy’s & St. Thomas NHS Trust, Guy's Hospital, London, United Kingdom
9Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy
10Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy
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Published July 9, 2024 - More info
Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated to epilepsy, autism and mild cortical abnormalities. However, their functional effects remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria as loss-of-function leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing wild-type RELN secretion in culture, animal models and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.