De Novo ARID1B mutations cause growth delay associated with aberrant Wnt/β–catenin signaling

Abstract

Haploinsufficiency of ARID1B (AT-rich interaction domain 1B) has been involved in autism spectrum disorder, nonsyndromic and syndromic intellectual disability, and corpus callosum agenesis. Growth impairment is a major clinical feature caused by ARID1B mutations; however, the mechanistic link has not been elucidated. Here, we confirm that growth delay is a common characteristic of patients with ARID1B mutations, which may be associated with dysregulation of the Wnt/β-catenin signaling pathway. An analysis of patients harboring pathogenic variants of ARID1B revealed that nearly half had short stature and nearly all had below-average height.Moreover, the percentage of patients with short stature increased with age.Knockdown of arid1b in zebrafish embryos markedly reduced body length and perturbed the expression of both chondrogenic and osteogenic genes including sox9a, col2a1a, runx2b, and col10a1. Knockout of Arid1b in chondrogenic ATDC5 cells inhibited chondrocyte proliferation and differentiation. Finally, Wnt/β-catenin signaling was perturbed in Arid1b-depleted zebrafish embryos and Arid1b knockout ATDC5 cells. These data indicate that ARID1B modulates bone growth possibly via regulation of the Wnt/β-catenin pathway, and may be an appropriate target for gene therapy in disorders of growth and development. K E Y W O R D SARID1B, bone growth, gene mutation, growth delay, short stature, Wnt/β-catenin

Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

“…This line, arid1b y607/+ (AB), is now available through ZIRC, though to our knowledge there have been no published reports of its use. Liu et al (2020), created a knockdown model of arid1b in zebrafish using morpholino oligonucleotide injection and analyzed embryonic growth as growth impairment is a major clinical feature of ARID1B mutations in humans. They also analyzed patients harboring pathogenic variants of ARID1B (Liu et al, 2020).…”

“…Liu et al (2020), created a knockdown model of arid1b in zebrafish using morpholino oligonucleotide injection and analyzed embryonic growth as growth impairment is a major clinical feature of ARID1B mutations in humans. They also analyzed patients harboring pathogenic variants of ARID1B (Liu et al, 2020). The authors found zebrafish embryos with knockdown in arid1b had both significantly reduced body length and trunk defects as well as perturbed expression of osteogenic genes and chondrogenic genes.…”

Differential roles of ARID1B in excitatory and inhibitory neural progenitors in the developing cortex

“…BRG1 has also been shown to physically interact with nuclear β-catenin at target gene promoters and facilitate transcriptional activation, most likely via chromatin remodeling 53 . A recent report confirms that ARID1B regulates Wnt/β-catenin signaling in HEK293T cells in a BRG1-dependent manner 54 . Vasileiou et al also reported that expression of β-catenin target genes is increased in peripheral blood lymphocytes taken from human patients with ARID1B loss-of-function mutations 37 .…”

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation inARID1B-related neurodevelopmental disorders

“…Wnt-β catenin signaling pathway was also found as enriched. An association between ARID1B and this specific pathway was suggested in recent studies 29,30 .…”