Mutations in core components of the spliceosome are responsible for a group of syndromes collectively known as spliceosomopathies. Patients exhibit microcephaly, micrognathia, malar hypoplasia, external ear anomalies, eye anomalies, psychomotor delay, intellectual disability, limb, and heart defects. Craniofacial malformations in these patients are predominantly found in neural crest cells‐derived structures of the face and head. Mutations in eight genes SNRPB , RNU4ATAC , SF3B4 , PUF60 , EFTUD2 , TXNL4 , EIF4A3 , and CWC27 are associated with craniofacial spliceosomopathies. In this review, we provide a brief description of the normal development of the head and the face and an overview of mutations identified in genes associated with craniofacial spliceosomopathies. We also describe a model to explain how and when these mutations are most likely to impact neural crest cells. We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing. Hence, disruption in splicing likely activates a cellular stress response that includes increased skipping of regulatory exons in genes such as MDM2 and MDM4 , key regulators of P53. This would result in P53‐associated death of neural crest cells and consequently craniofacial malformations associated with spliceosomopathies.

中文翻译：

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剪接体病和神经嵴：同一枚硬币的两个方面？

剪接体核心成分的突变导致了一组统称为剪接体病的综合征。患者表现出小头畸形、小颌畸形、颧骨发育不全、外耳异常、眼睛异常、精神运动迟缓、智力障碍、四肢和心脏缺陷。这些患者的颅面畸形主要见于面部和头部的神经嵴细胞衍生结构。8 个基因SNRPB、RNU4ATAC、SF3B4、PUF60、EFTUD2、TXNL4、EIF4A3和CWC27 的突变与颅面剪接体病有关。在这篇综述中，我们简要描述了头部和面部的正常发育，并概述了与颅面剪接体病相关的基因中发现的突变。我们还描述了一个模型来解释这些突变如何以及何时最有可能影响神经嵴细胞。我们推测核心剪接因子子集的突变会导致神经嵴细胞中的剪接中断，因为这些细胞对低效剪接的敏感性增加。因此，剪接的中断可能会激活细胞应激反应，包括增加MDM2和MDM4等基因中调节外显子的跳跃，P53的关键调节器。这将导致 P53 相关的神经嵴细胞死亡，从而导致与剪接体病相关的颅面畸形。