Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment

Elife. 2017 Jul 11:6:e25730. doi: 10.7554/eLife.25730.


Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.

Keywords: Coffin-Siris syndrome; autism spectrum disorders; endocrinology; experimental models of disease; human; human biology; medicine; mouse; neurodevelopmental disorders; neuroendocrine diseases; neuroscience.

MeSH terms

  • Animals
  • Behavior, Animal
  • Brain / pathology
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / physiopathology
  • Disease Models, Animal
  • Gene Expression Regulation
  • Growth Hormone-Releasing Hormone / metabolism
  • Haploinsufficiency*
  • Heterozygote
  • Insulin-Like Growth Factor I / metabolism
  • Mental Disorders / genetics*
  • Mental Disorders / physiopathology
  • Mice
  • Protein Serine-Threonine Kinases / metabolism
  • Transcription Factors / deficiency*


  • Arid1b protein, mouse
  • Transcription Factors
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Growth Hormone-Releasing Hormone
  • Snrk protein, mouse
  • Protein Serine-Threonine Kinases