Utami Kagistia Hana, Winata Cecilia Lanny, Hillmer Axel M, Aksoy Irene, Long Hoang Truong, Liany Herty, Chew Elaine G Y, Mathavan Sinnakaruppan, Tay Stacey K H, Korzh Vladimir, Sarda Pierre, Davila Sonia, Cacheux Valere
Human Genetics, Genome Institute of Singapore, Singapore, 138672; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597.
Hum Mutat. 2014 Nov;35(11):1311-20. doi: 10.1002/humu.22636. Epub 2014 Sep 23.
MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12;19) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full-length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short-hairpin RNA in ES-derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L-deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.
MED13L是中介体复合物的一个组成亚基，中介体是一种重要的转录调节因子，在真核生物中高度保守。在此，我们报告了一名患有皮埃尔-罗宾综合征、中度智力残疾、颅面畸形和肌肉缺陷的患者，其12号和19号染色体易位断点处存在MED13L破坏。该表型与先前描述的MED13L单倍体不足患者相似。在斑马鱼中敲低MED13L的同源物med13b，显示颅神经嵴细胞（NCCs）早期迁移缺陷，这导致后期软骨结构畸形，重现了人类患者中所见的颅面畸形。值得注意的是，我们在med13b morphant胚胎的不同脑区观察到发育中神经元的异常分布，在引入全长人类MED13L mRNA后这种异常分布可以得到挽救。为了与哺乳动物系统进行比较，我们在ES来源的人类神经祖细胞中通过短发夹RNA抑制MED13L表达，并将它们分化为神经元。转录组分析揭示了MED13L缺陷神经元中Wnt和FGF信号通路成分的差异表达。我们的发现为MED13L单倍体不足患者中针对NCCs衍生器官的重叠表型结果机制提供了新的见解，并强调了这些患者中临床上可识别的综合征表型。
