Mediator Complex Subunit 16(MED16,MIM:604062)is a member of the Mediator complex,which controls many aspects of transcriptional activity in all eukaryotes.Here,we report two individuals from a non-consanguineous famil...Mediator Complex Subunit 16(MED16,MIM:604062)is a member of the Mediator complex,which controls many aspects of transcriptional activity in all eukaryotes.Here,we report two individuals from a non-consanguineous family with biallelic variants in MED16 identified by exome sequencing.The affected individuals present with global developmental delay,intellectual disability,and dysmorphisms.To assess the pathogenicity of the variants,functional studies are performed in Drosophila and patient-derived cells.The fly ortholog med16 is expressed in neurons and some glia of the developing central nervous system(CNS).Loss of med16 leads to a reduction in eclosion and lifespan,as well as impaired synaptic transmission.In neurons differentiated from the patient-derived induced pluripotent stem cells(iPSCs),the neurite outgrowth is impaired and rescued by expression of exogenous MED16.The patient-associated variants behave as loss-of-function(LoF)alleles in flies and iPSCs.Additionally,the transcription of genes related to neuronal maturation and function is preferentially altered in patient cells relative to differentiated H9 controls.In summary,our findings support that MED16 is important for appropriate development and function,and that biallelic MED16 variants cause a neurodevelopmental disease.展开更多
基金supported by the National Key R&D Program of China (2020YFA0112500 and 2021YFA1100400)the National Natural Science Foundation of China (32271019 and 12411530079)+6 种基金the Natural Science Foundation of Shanghai Municipality (22ZR1462600)supported by the Natural Science Foundation of Hunan Province, China (2022JJ40206)Ruixin project of Hunan Provincial Maternal and Child Health Care Hospital (2023RX01)supported by the Clinical Research Center Projects for Genetic Birth Defects and Rare Diseases in Hunan Province (2023SK4053)Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province (2019SK1010)supported by the Model Organisms Screening Center of the UDN by U54NS093793 of the NIH (NINDS)supported by the Office of Research Infrastructure Programs of the NIH (awards R24 OD022005 and R24 OD031447).
文摘Mediator Complex Subunit 16(MED16,MIM:604062)is a member of the Mediator complex,which controls many aspects of transcriptional activity in all eukaryotes.Here,we report two individuals from a non-consanguineous family with biallelic variants in MED16 identified by exome sequencing.The affected individuals present with global developmental delay,intellectual disability,and dysmorphisms.To assess the pathogenicity of the variants,functional studies are performed in Drosophila and patient-derived cells.The fly ortholog med16 is expressed in neurons and some glia of the developing central nervous system(CNS).Loss of med16 leads to a reduction in eclosion and lifespan,as well as impaired synaptic transmission.In neurons differentiated from the patient-derived induced pluripotent stem cells(iPSCs),the neurite outgrowth is impaired and rescued by expression of exogenous MED16.The patient-associated variants behave as loss-of-function(LoF)alleles in flies and iPSCs.Additionally,the transcription of genes related to neuronal maturation and function is preferentially altered in patient cells relative to differentiated H9 controls.In summary,our findings support that MED16 is important for appropriate development and function,and that biallelic MED16 variants cause a neurodevelopmental disease.
