剪接体是一种大的核糖核蛋白复合物,可从mRNA前体转录物中去除内含子。EFTUD2中的突变,编码主要剪接体的一个组成部分,最近被确定为下颌面骨发育不良的原因,Guion-Almeida型(MFDGA),以下颌面骨发育不良为特征,小头畸形,外耳畸形和智力障碍。最近在患有特定颅面畸形的人类疾病中也发现了涉及剪接体功能或mRNA加工相关方面的其他几种基因的突变:Nager综合征中的SF3B4,肩面骨发育不全(AFD);SNRPB在脑孔下颌综合征中,以Robin序列和肋骨缺损为特征;EIF4A3在AFDRichieri-Costa-Pereira综合征中,以罗宾序列为特征,下颌骨正中裂和肢体缺损;和TXNL4A在Burn-McKeown综合征,涉及特定的颅面畸形。这里,我们回顾了这些综合征的表型和分子方面。鉴于颅面发育对mRNA加工缺陷的明显敏感性,与剪接体功能有关的其他蛋白质的突变可能会在未来引起相关的人类疾病。
The
spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNA transcripts. Mutations in EFTUD2, encoding a component of the major
spliceosome, have recently been identified as the cause of mandibulofacial dysostosis, Guion-Almeida type (MFDGA), characterized by mandibulofacial dysostosis, microcephaly, external ear malformations and intellectual disability. Mutations in several other genes involved in spliceosomal function or linked aspects of mRNA processing have also recently been identified in human disorders with specific craniofacial malformations: SF3B4 in Nager syndrome, an acrofacial dysostosis (AFD); SNRPB in cerebrocostomandibular syndrome, characterized by Robin sequence and rib defects; EIF4A3 in the AFD Richieri-Costa-Pereira syndrome, characterized by Robin sequence, median mandibular cleft and limb defects; and TXNL4A in Burn-McKeown syndrome, involving specific craniofacial dysmorphisms. Here, we
review phenotypic and molecular aspects of these syndromes. Given the apparent sensitivity of craniofacial development to defects in mRNA processing, it is possible that mutations in other proteins involved in spliceosomal function will emerge in the future as causative for related human disorders.