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.
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Contributors BHL, Y-MH and H-WY designed this study. MK and YJ performed most of the experiments. EK, MK, Y-SL, W-CS and YJ analysed the data. S-JL, Y-SL, D-CW, YHS, I-JB, WHS and W-CS performed some of the experiments. EK, IHC, E-JS, H-WY and BHL were involved in the diagnosis and treatment of the patient. EK, MK, YJ and BHL drafted and all authors revised the manuscript. All authors read and approved the final manuscript.
Funding This research was supported in part by the Bio & Medical Technology Development Programme of the national research Foundation (NRF) funded by the Korean government (NRF-2016M3A9B4915706 and NRF-2018M3A9H1078335).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the Institutional Review Board of the Asan Medical Center, Seoul, Korea (IRB number 2016-0768). The patient and her parents provided written informed consent to genetic testing.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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