Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature
- 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)
- 강민지; 강은구; 백인정; 서을주; 성영훈; 손우찬; 심우현; 우동철; 유한욱; 이범희; 이상준; 이용석; 주영희; 최인희; 한용만
- 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
- Authorize & License
-
- Files in This Item:
-
Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.