De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms
De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms
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DOI：
10.1016/j.ajhg.2016.08.001
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发表时间：
2016-10-06
影响因子：
9.8
通讯作者：
Muenke, Maximilian
中科院分区：
文献类型：
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作者：
Weiss, Karin;Terhal, Paulien A.;Muenke, Maximilian
染色体结构域解旋酶DNA结合蛋白4（Chromodomain helicase DNA binding protein 4，CHD 4）是一种ATP依赖的染色质重塑蛋白，参与基因转录、DNA修复和细胞周期进程的表观遗传调控。也被称为Mi2 beta，CHD 4是一个完整的亚基的一个良好的特征组蛋白脱乙酰酶复合物。在这里，我们报告了通过全外显子组测序和基于网络的基因匹配鉴定的CHD 4中具有从头错义取代的5个个体。这些个体具有重叠的表型，包括发育迟缓、智力残疾、听力损失、大头畸形、明显的面部畸形、腭异常、脑室扩大和性腺功能减退以及其他发现，如骨融合。变异体c.3380G>A（p.Arg1127Gln）、c.3443G>T（p.Trp1148Leu）、c.3518G>T（p.Arg1173Leu）和c.3008G>A（p.Gly1003Asp）（GenBank：NM_001273.3）影响进化上高度保守的残基，并且预测是有害的。先前在酵母中的研究表明，等同的Arg 1127和Trp 1148残基对SNF 2功能至关重要。此外，在恶性肿瘤中报告了相同位置的突变，SMARCA 4 C-末端解旋酶结构域中等同精氨酸残基的从头错义取代与Coffin Sins综合征相关。对p.Arg1127Gln和p.Arg1173Leu突变体的基于细胞的研究证明了正常的细胞核定位和HDAC 1相互作用。基于这些发现，突变可能会改变复合物的活性，但不会改变其形成。本报告提供了证据CHD 4在人类发育中的作用，并扩大了一个日益认可的孟德尔疾病组，涉及染色质重塑和修饰。
Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2 beta., CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Sins syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.