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Impaired Development of Neural‐Crest Cell‐Derived Organs and Intellectual Disability Caused by MED13L Haploinsufficiency
Author(s) -
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
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22636
Subject(s) - haploinsufficiency , biology , neural crest , zebrafish , morpholino , phenotype , wnt signaling pathway , neural development , craniofacial , genetics , microbiology and biotechnology , embryo , gene
MED13L is a component subunit of the M ediator 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 P ierre– R obin 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 ( NCC s) 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 m RNA . 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 W nt and FGF signaling pathways in MED13L‐ deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCC s derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.