Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects

Nat Neurosci. 2015 Dec;18(12):1731-6. doi: 10.1038/nn.4169.

Dennis Mircsof ¹ ², Maéva Langouët ³, Marlène Rio ³ ⁴, Sébastien Moutton ³, Karine Siquier-Pernet ³, Christine Bole-Feysot ⁵, Nicolas Cagnard ⁶, Patrick Nitschke ⁶, Ludmila Gaspar ¹, Matej Žnidarič ¹, Olivier Alibeu ⁵, Ann-Kristina Fritz ⁷, David P Wolfer ⁷, Aileen Schröter ⁸, Giovanna Bosshard ², Markus Rudin ⁸, Christina Koester ², Florence Crestani ², Petra Seebeck ⁹, Nathalie Boddaert ³ ¹⁰, Katrina Prescott ¹¹, DDD Study, Rochelle Hines ¹², Steven J Moss ¹², Jean-Marc Fritschy ², Arnold Munnich ³, Jeanne Amiel ³ ⁴, Steven A Brown ¹, Shiva K Tyagarajan ², Laurence Colleaux ³

Affiliations

1 Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
2 Neuromorphology Group, Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
3 INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
4 Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.
5 Genomic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
6 Bioinformatic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
7 Institute of Anatomy, University of Zürich and Institute of Human Movement Sciences and Sport, ETH Zürich, Switzerland.
8 Molecular Imaging and Functional Pharmacology Group, University of Zürich, Zürich, Switzerland.
9 Center for Integrative Rodent Physiology, University of Zürich, Zürich, Switzerland.
10 Service de radiologie pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.
11 Yorkshire Regional Genetics Service, Leeds Teaching Hospitals National Health Service Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Chapeltown Road, Leeds, UK.
12 Tufts University, Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, USA.

PMID: 26571461 DOI: 10.1038/nn.4169

Abstract

The NONO protein has been characterized as an important transcriptional regulator in diverse cellular contexts. Here we show that loss of NONO function is a likely cause of human intellectual disability and that NONO-deficient mice have cognitive and affective deficits. Correspondingly, we find specific defects at inhibitory synapses, where NONO regulates synaptic transcription and gephyrin scaffold structure. Our data identify NONO as a possible neurodevelopmental disease gene and highlight the key role of the DBHS protein family in functional organization of GABAergic synapses.

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