Biallelic <i>MED16</i> variants disrupt neural development and lead to an intellectual disability syndrome

Yan Huang; Zhenglong Xiang; Yaqin Xiang; Hu Pan; Mei He; Zhenming Guo; Oguz Kanca; Chen Liu; Zhao Zhang; Huaizhe Zhan; Yuan Wang; Qing-Ran Bai; Hugo J. Bellen; Hua Wang; Shan Bian; Xiao Mao

doi:10.1016/j.jgg.2025.04.004

Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome

doi: 10.1016/j.jgg.2025.04.004

a. Department of Medical Genetics & Pediatric Research Institute, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University, (Hunan Children's Hospital), Changsha, Hunan 410007, China;
b. Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China;
c. Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University, (Hunan Children's Hospital), Changsha, Hunan 410007, China;
d. National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, Hunan 410008, China;
e. Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA;
f. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA;
g. Neonatology, Children's Hospital Affiliated to Shandong University, Jinan, Shandong 250022, China;
h. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China;
i. China Regional Research Center, International Center for Genetic Engineering and Biotechnology, Taizhou, Jiangsu 225316, China;
j. Department of Medical Genetics, Maternal and Child Health Hospital of Hunan Province, Changsha, Hunan 410008, China

基金项目:

Guo for importing the fly strains, and the Drosophila Genomics Resource Center for cDNA. S. Bian is supported by the National Key R&D Program of China (2020YFA0112500 and 2021YFA1100400), the National Natural Science Foundation of China (32271019 and 12411530079), and the Natural Science Foundation of Shanghai Municipality (22ZR1462600). X. Mao is supported by Natural Science Foundation of Hunan Province, China (2022JJ40206) and Ruixin project of Hunan Provincial Maternal and Child Health Care Hospital (2023RX01). H. Wang is supported by the Clinical Research Center Projects for Genetic Birth Defects and Rare Diseases in Hunan Province (2023SK4053) and Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province (2019SK1010). H. J. Bellen is supported through the Model Organisms Screening Center of the UDN by U54NS093793 of the NIH (NINDS). H. J. Bellen and O. Kanca are supported by the Office of Research Infrastructure Programs of the NIH (awards R24 OD022005 and R24 OD031447).

We thank the family for their participation. We thank the Bloomington Drosophila Stock Center for providing stock, X.&thinsp

详细信息

通讯作者:
Shan Bian,E-mail:shan_bian@tongji.edu.cn

Xiao Mao,E-mail:gbtechies@outlook.com

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出版历程
- 收稿日期: 2024-10-29
- 录用日期: 2025-04-06
- 修回日期: 2025-04-03
- 网络出版日期: 2025-07-11

Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome

a. Department of Medical Genetics & Pediatric Research Institute, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University, (Hunan Children's Hospital), Changsha, Hunan 410007, China;
b. Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China;
c. Department of Medical Genetics, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University, (Hunan Children's Hospital), Changsha, Hunan 410007, China;
d. National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, University of South China, Changsha, Hunan 410008, China;
e. Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA;
f. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA;
g. Neonatology, Children's Hospital Affiliated to Shandong University, Jinan, Shandong 250022, China;
h. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China;
i. China Regional Research Center, International Center for Genetic Engineering and Biotechnology, Taizhou, Jiangsu 225316, China;
j. Department of Medical Genetics, Maternal and Child Health Hospital of Hunan Province, Changsha, Hunan 410008, China

Funds:

We thank the family for their participation. We thank the Bloomington Drosophila Stock Center for providing stock, X.&thinsp

摘要

摘要:
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.
- MED16 /
- Intellectual disability /
- Loss-of-function variants /
- Transcriptional regulation /
- Drosophila /
- Patient derived iPSCs
Abstract:
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.
- MED16 /
- Intellectual disability /
- Loss-of-function variants /
- Transcriptional regulation /
- Drosophila /
- Patient derived iPSCs

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Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome

doi: 10.1016/j.jgg.2025.04.004

通讯作者:
Shan Bian,E-mail:shan_bian@tongji.edu.cn

Xiao Mao,E-mail:gbtechies@outlook.com

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Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome

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Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome

doi: 10.1016/j.jgg.2025.04.004

通讯作者: Shan Bian,E-mail:shan_bian@tongji.edu.cn Xiao Mao,E-mail:gbtechies@outlook.com

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出版历程

Biallelic MED16 variants disrupt neural development and lead to an intellectual disability syndrome

计量

出版历程

目录

通讯作者:
Shan Bian,E-mail:shan_bian@tongji.edu.cn

Xiao Mao,E-mail:gbtechies@outlook.com