PDF(Pubmed)
Abstract：
Neurodevelopmental disorders (NDDs) include a broad spectrum of pathological conditions that affect >4% of children worldwide, share common features and present a variegated genetic origin. They include clinically defined diseases, such as autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), motor disorders such as Tics and Tourette\'s syndromes, but also much more heterogeneous conditions like intellectual disability (ID) and epilepsy. Schizophrenia (SCZ) has also recently been proposed to belong to NDDs. Relatively common causes of NDDs are copy number variations (CNVs), characterised by the gain or the loss of a portion of a chromosome. In this review, we focus on deletions and duplications at the 16p11.2 chromosomal region, associated with NDDs, ID, ASD but also epilepsy and SCZ. Some of the core phenotypes presented by human carriers could be recapitulated in animal and cellular models, which also highlighted prominent neurophysiological and signalling alterations underpinning 16p11.2 CNVs-associated phenotypes. In this review, we also provide an overview of the genes within the 16p11.2 locus, including those with partially known or unknown function as well as non-coding RNAs. A particularly interesting interplay was observed between MVP and MAPK3 in modulating some of the pathological phenotypes associated with the 16p11.2 deletion. Elucidating their role in intracellular signalling and their functional links will be a key step to devise novel therapeutic strategies for 16p11.2 CNVs-related syndromes.
摘要：
神经发育障碍（NDD）包括广泛的病理状况，影响全球>4％的儿童，具有共同的特征，并呈现出多样化的遗传起源。它们包括临床定义的疾病，如自闭症谱系障碍（ASD），注意缺陷/多动障碍（ADHD），运动障碍，如Tics和Tourette综合征，但也有更多的异质性条件，如智力残疾（ID）和癫痫。最近还提出精神分裂症(SCZ)属于NDD。NDD的相对常见原因是拷贝数变异(CNVs)，以染色体的一部分的增加或丢失为特征。在这次审查中,我们关注16p11.2染色体区域的缺失和重复，与NDD相关，ID,ASD还有癫痫和SCZ。人类携带者呈现的一些核心表型可以在动物和细胞模型中概括，这也突出了16p11.2CNVs相关表型的突出神经生理和信号改变。在这次审查中,我们还提供了16p11.2基因座内的基因的概述，包括具有部分已知或未知功能的RNA以及非编码RNA。在调节与16p11.2缺失相关的一些病理表型中,在MVP和MAPK3之间观察到特别有趣的相互作用。阐明它们在细胞内信号传导中的作用及其功能联系将是设计16p11.2CNVs相关综合征的新治疗策略的关键步骤。
