Impaired Development Of Neural-Crest Cell Derived Organs and Intellectual Disability Caused By MED13L Haploinsufficiency

Utami, K.H., Winata, C.L., Hillmer, A.M., Aksoy, I., Long, H.T., Liany, H., Yan, E.C., Mathavan, S., Hong, S.T., Korzh, V., Sarda, P., Davila, S., Cacheux, V.
Human Mutation   35(11): 1311-20 (Journal)
Registered Authors
Korzh, Vladimir, Mathavan, S., Winata, Cecilia Lanny
MED13L, craniofacial dysmorphism, neural crest, next-generation sequencing, zebrafish model
MeSH Terms
  • Animals
  • Cell Differentiation/genetics
  • Cell Movement/genetics
  • Child, Preschool
  • Chromosome Breakpoints
  • Disease Models, Animal
  • Embryonic Stem Cells/metabolism
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Genetic Association Studies
  • Haploinsufficiency*
  • Humans
  • Intellectual Disability/diagnosis
  • Intellectual Disability/genetics*
  • Mediator Complex/genetics*
  • Mediator Complex/metabolism
  • Neural Crest/embryology
  • Neural Crest/metabolism*
  • Neurons/cytology
  • Neurons/metabolism
  • Phenotype
  • RNA, Messenger/genetics
  • Sequence Analysis, DNA
  • Transcriptome
  • Translocation, Genetic
  • Zebrafish
25137640 Full text @ Hum. Mutat.
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 (ID), 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 into 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 signalling 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. This article is protected by copyright. All rights reserved.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes