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Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature

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Abstract
Background ARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with ARID2 mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway. Methods The phenotypes of 22 patients with either an ARID2 heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with ARID2 haploinsufficiency as well as using the mouse model of Arid2 haploinsufficiency by CRISPR/Cas9 gene editing. Results The phenotypic characteristics of ARID2 deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient ARID2 knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, Arid2 haploinsufficient mice exhibited reduced body size and learning/memory deficit. ARID2 haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation. Discussion ARID2 haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.
Author(s)
강민지강은구백인정서을주성영훈손우찬심우현우동철유한욱이범희이상준이용석주영희최인희한용만
Issued Date
2021
Type
Article
Keyword
genetics
DOI
10.1136/jmedgenet-2020-107111
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7610
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2451131190&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Association%20between%20ARID2%20and%20RAS-MAPK%20pathway%20in%20intellectual%20disability%20and%20short%20stature&offset=0&pcAvailability=true
Publisher
JOURNAL OF MEDICAL GENETICS
Location
영국
Language
영어
ISSN
0022-2593
Citation Volume
58
Citation Number
1
Citation Start Page
767
Citation End Page
777
Appears in Collections:
Medicine > Medicine
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