Haploinsufficiency of MED13L impairs development of neural-crest cell derived organs and contributes to intellectual disability. Homo sapiens

MED13L is a component subunit of Mediator complex that is known to act as transcriptional repressor within Cdk8 Module for RNA polymerase II-dependent transcription. Previous studies have identified mutations or structural variants (SVs) affecting MED13L in patients with heart defects, craniofacial anomalies and intellectual disability (ID). Here, we reported MED13L disruption in a translocation t(12;19) breakpoint in a patient with Pierre-Robin syndrome, mild intellectual disability (ID), craniofacial abnormalities, and muscular defects. Knockdown of MED13L orthologue in zebrafish showed delayed migration of cranial neural crest cells (NCCs), cartilage structure deformities and abnormal distribution of developing neurons, recapitulating defects observed in these patients. Co-injection of human MED13L mRNA rescued the severe phenotype observed in the zebrafish morphants. To compare with human system, we differentiated neurons from ES-derived human neural progenitors and suppressed MED13L expression by short-hairpin RNA, and further investigated the genome-wide expression profile of these cells. Wnt-related genes and FGFR3 were significantly differentially expressed upon MED13L knockdown, which showed the functional link between neural-crest induction and specifications regulated by activation of Wnt and FGF signaling pathway. Our finding provides an insight into possible mechanism of diverse phenotypic outcome targeting neural-crest cells derived organs in patients with MED13L haploinsufficiency.