De Novo ARID1B mutations cause growth delay associated with aberrant Wnt/β-catenin signaling
De Novo ARID1B mutations cause growth delay associated with aberrant Wnt/β-catenin signaling
复制标题
从头 ARID1B 突变导致与异常 Wnt/β-catenin 信号传导相关的生长延迟
DOI：
10.1002/humu.23990
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发表时间：
2020-03-03
期刊：
影响因子：
3.9
通讯作者：
Yu, Yongguo
中科院分区：
文献类型：
--
作者：
Liu, Xiaomin;Hu, Guorui;Yu, Yongguo
ARID 1B（AT丰富的相互作用结构域1B）的单倍不足已涉及自闭症谱系障碍，非综合征和综合征性智力残疾，胼胝体发育不全。生长障碍是由ARID 1B突变引起的主要临床特征;然而，机制联系尚未阐明。在这里，我们证实生长延迟是ARID 1B突变患者的共同特征，这可能与Wnt/β-连环蛋白信号通路的失调有关。对携带ARID 1B致病性变体的患者进行的分析显示，近一半的患者身材矮小，几乎所有人的身高都低于平均水平。此外，身材矮小患者的百分比随着年龄的增长而增加。在斑马鱼胚胎中敲低arid 1b基因会显著缩短体长，扰乱软骨和成骨基因的表达，包括sox 9a，col 2a 1a，runx 2b和col 10a 1。敲除软骨形成ATDC 5细胞中的Arid 1b抑制软骨细胞增殖和分化。最后，Wnt/β-连环蛋白信号在Arid 1b缺失的斑马鱼胚胎和Arid 1b敲除的ATDC 5细胞中受到干扰。这些数据表明，ARID 1B可能通过调节Wnt/β-连环蛋白通路来调节骨生长，并且可能是生长和发育障碍的基因治疗的适当靶点。
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/beta-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/beta-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/beta-catenin pathway, and may be an appropriate target for gene therapy in disorders of growth and development.