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

Celen, C; Chuang, J-C; Luo, X; Nijem, N; Walker, AK; Chen, F; Zhang, S; Chung, AS; Nguyen, LH; Nassour, I; et al. Celen, C; Chuang, J-C; Luo, X; Nijem, N; Walker, AK; Chen, F; Zhang, S; Chung, AS; Nguyen, LH; Nassour, I; Budhipramono, A; Sun, X; Bok, LA; McEntagart, M; Gevers, EF; Birnbaum, SG; Eisch, AJ; Powell, CM; Ge, W-P; Santen, GW; Chahrour, M; Zhu, H (2017) Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. Elife, 6. e25730. ISSN 2050-084X https://doi.org/10.7554/eLife.25730
SGUL Authors: McEntagart, Meriel

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Abstract

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.

Item Type: Article
Additional Information: Copyright Celen et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Keywords: Coffin-Siris syndrome, autism spectrum disorders, endocrinology, experimental models of disease, human, human biology, medicine, mouse, neurodevelopmental disorders, neuroendocrine diseases, neuroscience
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Elife
ISSN: 2050-084X
Language: eng
Dates:
DateEvent
11 July 2017Published
24 June 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
PubMed ID: 28695822
Web of Science ID: WOS:000405668200001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109053
Publisher's version: https://doi.org/10.7554/eLife.25730

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