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Hum Mol Genet. 2018 Jun 15;27(12):2138-2153. doi: 10.1093/hmg/ddy122.

A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations.

Author information

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 67404 Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U1258, 67404 Illkirch, France.
CELPHEDIA, PHENOMIN, Institut Clinique de la Souris, 67404 Illkirch, France.
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, The Netherlands.
Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital Femmes Mères Enfants, Hospices Civils de Lyon, Institut des Sciences Cognitives, CNRS UMR5304, Université Claude Bernard Lyon1, 69675 Bron, France.
Team Synapse in Cognition, Institut Interdisciplinaire de NeuroScience, Centre National de la Recherche Scientifique CNRS UMR5297, Université de Bordeaux, 33077 Bordeaux, France.
Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 29200 Brest, France.
Pole In Vivo, Institut Interdisciplinaire de NeuroScience, Centre National de la Recherche Scientifique CNRS UMR5297, Université de Bordeaux, 33077 Bordeaux, France.
Service de Diagnostic Génétique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France.


The aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans, among which the most frequent, a 24 bp duplication in the polyalanine tract 2 (c.428_451dup24), gives rise to intellectual disability, fine motor defects with or without epilepsy. To understand the functional consequences of this mutation, we generated a partially humanized mouse model carrying the c.428_451dup24 duplication (Arxdup24/0) that we characterized at the behavior, neurological and molecular level. Arxdup24/0 males presented with hyperactivity, enhanced stereotypies and altered contextual fear memory. In addition, Arxdup24/0 males had fine motor defects with alteration of reaching and grasping abilities. Transcriptome analysis of Arxdup24/0 forebrains at E15.5 showed a down-regulation of genes specific to interneurons and an up-regulation of genes normally not expressed in this cell type, suggesting abnormal interneuron development. Accordingly, interneuron migration was altered in the cortex and striatum between E15.5 and P0 with consequences in adults, illustrated by the defect in the inhibitory/excitatory balance in Arxdup24/0 basolateral amygdala. Altogether, we showed that the c.428_451dup24 mutation disrupts Arx function with a direct consequence on interneuron development, leading to hyperactivity and defects in precise motor movement control and associative memory. Interestingly, we highlighted striking similarities between the mouse phenotype and a cohort of 33 male patients with ARX c.428_451dup24, suggesting that this new mutant mouse line is a good model for understanding the pathophysiology and evaluation of treatment.

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