Ramond Francis, Dalgliesh Caroline, Grimmel Mona, Wechsberg Oded, Vetro Annalisa, Guerrini Renzo, FitzPatrick David, Poole Rebecca L, Lebrun Marine, Bayat Allan, Grasshoff Ute, Bertrand Miriam, Witt Dennis, Turnpenny Peter D, Faundes Víctor, Santa María Lorena, Mendoza Fuentes Carolina, Mabe Paulina, Hussain Shaun A, Mullegama Sureni V, Torti Erin, Oehl-Jaschkowitz Barbara, Salmon Lina Basel, Orenstein Naama, Shahar Noa Ruhrman, Hagari Ofir, Bazak Lily, Hoffjan Sabine, Prada Carlos E, Haack Tobias, Elliott David J
Service de Génétique, Hôpital Nord, CHU Saint-Etienne, Saint-Etienne, France.
Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Genet Med. 2023 Apr;25(4):100003. doi: 10.1016/j.gim.2022.100003. Epub 2022 Dec 20.
Transformer2 proteins (Tra2α and Tra2β) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder.
A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2β-1 and Tra2β-3 isoforms from patient-derived cells were performed. Tra2β1-GFP, Tra2β3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells.
All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform. All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2β-1 isoform, whereas they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1.
Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein.
Transformer2蛋白（Tra2α和Tra2β）控制人类细胞中的剪接模式，且这些基因的种系变异未与任何人类表型相关联。本研究的目的是将TRA2B基因的种系变异与一种新型神经发育障碍相关联。
招募了来自11个无关家庭的12名个体，他们携带预测的功能丧失单等位基因变异，大多为新发变异。对患者来源细胞中的Tra2β-1和Tra2β-3亚型进行了RNA测序和蛋白质印迹分析。将Tra2β1-GFP、Tra2β3-GFP和CHEK1外显子3质粒转染到HEK-293细胞中。
所有变异都聚集在TRA2B的5'部分，位于负责非经典Tra2β-3亚型表达的可变翻译起始位点上游。所有受影响个体均表现出智力残疾和/或发育迟缓，常伴有婴儿痉挛、小头畸形、脑异常、自闭症谱系障碍、喂养困难和身材矮小。实验研究表明，这些变异降低了经典Tra2β-1亚型的表达，而增加了较短且缺乏N端RS1结构域的Tra2β-3亚型的表达。结果显示，Tra2β-3-GFP表达增加会干扰CHEK1外显子3掺入其成熟转录本，而正常情况下该过程由Tra2β-1完成。
聚集在TRA2B 5'部分的预测功能丧失变异通过一种明显的显性负性疾病机制导致一种新的神经发育综合征，该机制涉及使用可变翻译起始位点和较短的抑制性Tra2β蛋白的过表达。
