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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Child
  • Child, Preschool
  • Cholinergic Neurons / metabolism
  • Cholinergic Neurons / pathology
  • Contracture
  • Disease Models, Animal
  • Epilepsy / genetics*
  • Epilepsy / physiopathology
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics*
  • Humans
  • Infant
  • Intellectual Disability
  • Male
  • Mice
  • Mutation
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / physiopathology
  • Peptides / genetics
  • Prosencephalon / physiopathology
  • Spastic Paraplegia, Hereditary
  • Transcription Factors / genetics*
  • Transcriptome / genetics
  • Young Adult


  • ARX protein, human
  • ARX protein, mouse
  • Homeodomain Proteins
  • Peptides
  • Transcription Factors
  • polyalanine

Supplementary concepts

  • Spastic Paraplegia 18, Autosomal Recessive