当前位置: X-MOL 学术Am. J. Med. Genet. Semin. Med. Genet. Part C › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The NuRD complex and macrocephaly associated neurodevelopmental disorders.
American Journal of Medical Genetics Seminars in Medical Genetics, Part C ( IF 2.8 ) Pub Date : 2019-11-18 , DOI: 10.1002/ajmg.c.31752
Tyler Mark Pierson 1, 2, 3 , Maria G Otero 3 , Katheryn Grand 4 , Andrew Choi 3 , John M Graham 4 , Juan I Young 5 , Joel P Mackay 6
Affiliation  

The nucleosome remodeling and deacetylase (NuRD) complex is a major regulator of gene expression involved in pluripotency, lineage commitment, and corticogenesis. This important complex is composed of seven different proteins, with mutations in CHD3, CHD4, and GATAD2B being associated with neurodevelopmental disorders presenting with macrocephaly and intellectual disability similar to other overgrowth and intellectual disability (OGID) syndromes. Pathogenic variants in CHD3 and CHD4 primarily involve disruption of enzymatic function. GATAD2B variants include loss-of-function mutations that alter protein dosage and missense variants that involve either of two conserved domains (CR1 and CR2) known to interact with other NuRD proteins. In addition to macrocephaly and intellectual disability, CHD3 variants are associated with inguinal hernias and apraxia of speech; whereas CHD4 variants are associated with skeletal anomalies, deafness, and cardiac defects. GATAD2B-associated neurodevelopmental disorder (GAND) has phenotypic overlap with both of these disorders. Of note, structural models of NuRD indicate that CHD3 and CHD4 require direct contact with the GATAD2B-CR2 domain to interact with the rest of the complex. Therefore, the phenotypic overlaps of CHD3- and CHD4-related disorders with GAND are consistent with a loss in the ability of GATAD2B to recruit CHD3 or CHD4 to the complex. The shared features of these neurodevelopmental disorders may represent a new class of OGID syndrome: the NuRDopathies.

中文翻译:

NuRD复合体和大头畸形相关的神经发育障碍。

核小体重塑和脱乙酰基酶(NuRD)复合物是涉及多能性,谱系承诺和皮质发生的基因表达的主要调节剂。这个重要的复合物由七种不同的蛋白质组成,其中CHD3,CHD4和GATAD2B的突变与神经发育障碍有关,后者表现出与其他过度生长和智力障碍(OGID)综合征类似的大头畸形和智力障碍。CHD3和CHD4中的致病变异主要涉及酶功能的破坏。GATAD2B变体包括改变蛋白质剂量的功能丧失突变和涉及两个已知与其他NuRD蛋白相互作用的保守域(CR1和CR2)之一的错义变体。除了大头和智力障碍之外,CHD3变异与腹股沟疝和言语失用有关。而CHD4变异与骨骼异常,耳聋和心脏缺陷有关。GATAD2B相关的神经发育障碍(GAND)与这两种疾病都有表型重叠。值得注意的是,NuRD的结构模型表明CHD3和CHD4需要与GATAD2B-CR2域直接接触才能与复合物的其余部分相互作用。因此,CHD3和CHD4相关疾病与GAND的表型重叠与GATAD2B将CHD3或CHD4募集到复合物中的能力丧失一致。这些神经发育障碍的共同特征可能代表了一类新的OGID综合征:NuRDopathies。GATAD2B相关的神经发育障碍(GAND)与这两种疾病都有表型重叠。值得注意的是,NuRD的结构模型表明CHD3和CHD4需要与GATAD2B-CR2域直接接触才能与复合物的其余部分相互作用。因此,CHD3和CHD4相关疾病与GAND的表型重叠与GATAD2B将CHD3或CHD4募集到复合物中的能力丧失一致。这些神经发育障碍的共同特征可能代表了一类新的OGID综合征:NuRDopathies。GATAD2B相关的神经发育障碍(GAND)与这两种疾病都有表型重叠。值得注意的是,NuRD的结构模型表明CHD3和CHD4需要与GATAD2B-CR2域直接接触才能与复合物的其余部分相互作用。因此,CHD3和CHD4相关疾病与GAND的表型重叠与GATAD2B将CHD3或CHD4募集到复合物中的能力丧失一致。这些神经发育障碍的共同特征可能代表了一类新的OGID综合征:NuRDopathies。CHD3和CHD4相关疾病与GAND的表型重叠与GATAD2B将CHD3或CHD4募集到复合物中的能力丧失一致。这些神经发育障碍的共同特征可能代表了一类新的OGID综合征:NuRDopathies。CHD3和CHD4相关疾病与GAND的表型重叠与GATAD2B将CHD3或CHD4募集到复合物中的能力丧失一致。这些神经发育障碍的共同特征可能代表了一类新的OGID综合征:NuRDopathies。
更新日期:2019-11-01
down
wechat
bug