title: Impaired development of neural-crest cell-derived organs and intellectual disability caused by MED13L haploinsufficiency.
abstract: 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.
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore, 138672; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597.
authors.forename: Kagistia Hana
authors.initials: KH
authors.lastname: Utami
authors.forename: Cecilia Lanny
authors.initials: CL
authors.lastname: Winata
authors.forename: Axel M
authors.initials: AM
authors.lastname: Hillmer
authors.forename: Irene
authors.initials: I
authors.lastname: Aksoy
authors.forename: Hoang Truong
authors.initials: HT
authors.lastname: Long
authors.forename: Herty
authors.initials: H
authors.lastname: Liany
authors.forename: Elaine G Y
authors.initials: EG
authors.lastname: Chew
authors.forename: Sinnakaruppan
authors.initials: S
authors.lastname: Mathavan
authors.forename: Stacey K H
authors.initials: SK
authors.lastname: Tay
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korzh
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.forename: Valere
authors.initials: V
authors.lastname: Cacheux
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D057895:Haploinsufficiency; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D009432:Neural Crest / Q000196:embryology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA; D059467:Transcriptome; D014178:Translocation, Genetic; D015027:Zebrafish
chemical_list: C480067:MED13L protein, human; D056892:Mediator Complex; D012333:RNA, Messenger
keywords: MED13L; craniofacial dysmorphism; neural crest; next-generation sequencing; zebrafish model