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

Abstract

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 <i>ARID2</i> mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway. The phenotypes of 22 patients with either an <i>ARID2</i> heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with <i>ARID2</i> haploinsufficiency as well as using the mouse model of <i>Arid2</i> haploinsufficiency by CRISPR/Cas9 gene editing. The phenotypic characteristics of <i>ARID2</i> deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient <i>ARID2</i> 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, <i>Arid2</i> haploinsufficient mice exhibited reduced body size and learning/memory deficit. <i>ARID2</i> haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation. <i>ARID2</i> 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.