Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype
Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype
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DOI：
10.1007/s00439-017-1757-z
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发表时间：
2017-03-01
期刊：
影响因子：
5.3
通讯作者：
Wieczorek, D.
中科院分区：
文献类型：
--
作者：
Bramswig, Nuria C.;Caluseriu, O.;Wieczorek, D.
染色质重塑是一个塑造核小体格局的复杂过程，从而调节转录因子对靶基因调节区的可及性，最终管理基因表达。SWI/SNF(开关/蔗糖不可发酵)复合体以一种依赖于ATP的方式重塑核小体结构，分为两个主要亚类：梵天相关因子(BAF)和多溴梵天相关因子(PBAF)复合体。SWI/SNF复合体亚单位的体细胞突变与不同的癌症有关，而胚系突变与自闭症谱系障碍以及神经发育障碍Coffin-Siris和Nicolades-Baraitser综合征(NCBRS)有关。CS的特征是智力残疾(ID)、面部粗大、第五指和/或脚趾甲发育不全或缺失。到目前为止，已发现5个SWI/SNF亚单位编码基因ARID1B、SMARCA4、SMARCB1、ARID1A和SMARCE1的变异以及转录因子编码基因sox11的变异。ARID2是PBAF亚复合体的成员，直到最近才被认为与任何神经发育表型有关。2015年，ARID2基因突变被认为与智力残疾有关。在这项研究中，我们报告了两个患有ARID2基因移码突变的个体。这两个人都有类似于css的表型，包括ID，面部特征粗化，其他可识别的面部变形和第五趾甲发育不良。因此，这项研究确定ARID2基因突变是一种新的和罕见的导致CS样表型的原因，并扩大了CS样基因的列表。
Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin-Siris (CSS) and Nicolaides-Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes ARID1B, SMARCA4, SMARCB1, ARID1A, and SMARCE1 as well as variants in the transcription factor-encoding gene SOX11 have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the ARID2 gene were associated with intellectual disability. In this study, we report on two individuals with private de novo ARID2 frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the ARID2 gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.