Pathogenicity of Mediator Complex Subunit 27 ( <i>MED27</i> ) in a Neurodevelopmental Disorder with Cerebellar Atrophy

Neurodevelopmental disorders (NDDs) affect brain function and development, with 90% lacking approved treatments. Understanding their pathogenic mechanisms is critical for developing precision gene therapies. An autosomal recessive NDD associated with variants in the Mediator complex subunit 27 (MED27) gene is previously identified. The Mediator complex is essential for transcription initiation by bridging transcription factors (TFs) at enhancers to RNA polymerase II at promoters. All patients with MED27 variants exhibit cerebellar hypoplasia or atrophy, underscoring the cerebellum's heightened vulnerability to MED27 dysfunction. To investigate the disease mechanisms, in vitro stem cells carrying patient-specific MED27 variants and in vivo mouse models with Med27 loss-of-function (LoF) are generated. These preclinical models recapitulate key patient phenotypes, including progressive cerebellar atrophy and motor deficits. Molecular analyses reveal that mutant MED27 destabilizes the Mediator complex, impairing its chromatin occupancy and altering chromatin interactions. Comprehensive transcriptomic profiling, including single-cell resolution spatial transcriptomics, identifies dysregulation of downstream targets regulated by MED27, such as critical master regulatory TFs involved in neurogenesis and cerebellar development. This study elucidates a partial LoF mechanism underlying MED27-associated NDDs and establishes a prototype for investigating NDDs caused by pathogenic variants in Mediator subunits.

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Publication Details

Journal
Advanced Science
Published
2025-09-29
DOI
https://doi.org/10.1002/advs.202505535
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
0.00
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article

Pathogenicity of Mediator Complex Subunit 27 ( MED27 ) in a Neurodevelopmental Disorder with Cerebellar Atrophy

Kin Ming Kwan, Hoi‐Hung Cheung, Liao‐Kuo Gong, Y.C. Lui et al.
Advanced Science
RNA modifications and cancer
article

Pathogenicity of Mediator Complex Subunit 27 ( MED27 ) in a Neurodevelopmental Disorder with Cerebellar Atrophy

Kin Ming Kwan, Hoi‐Hung Cheung, Liao‐Kuo Gong, Y.C. Lui, Linyan Meng, Yulong Qiao, Yang‐Xin Fu, Yong Lei, Huating Wang, Shen Gu, Pengfei Lin, Xiaocheng Li, Nuo Chen, Lijun Yuan, Tianyu Guo, Zhou Haiying, Ho Ko, Xiao Chen, Nuermila Yiliyaer
article en

Abstract

Neurodevelopmental disorders (NDDs) affect brain function and development, with 90% lacking approved treatments. Understanding their pathogenic mechanisms is critical for developing precision gene therapies. An autosomal recessive NDD associated with variants in the Mediator complex subunit 27 (MED27) gene is previously identified. The Mediator complex is essential for transcription initiation by bridging transcription factors (TFs) at enhancers to RNA polymerase II at promoters. All patients with MED27 variants exhibit cerebellar hypoplasia or atrophy, underscoring the cerebellum's heightened vulnerability to MED27 dysfunction. To investigate the disease mechanisms, in vitro stem cells carrying patient-specific MED27 variants and in vivo mouse models with Med27 loss-of-function (LoF) are generated. These preclinical models recapitulate key patient phenotypes, including progressive cerebellar atrophy and motor deficits. Molecular analyses reveal that mutant MED27 destabilizes the Mediator complex, impairing its chromatin occupancy and altering chromatin interactions. Comprehensive transcriptomic profiling, including single-cell resolution spatial transcriptomics, identifies dysregulation of downstream targets regulated by MED27, such as critical master regulatory TFs involved in neurogenesis and cerebellar development. This study elucidates a partial LoF mechanism underlying MED27-associated NDDs and establishes a prototype for investigating NDDs caused by pathogenic variants in Mediator subunits.

Advanced ScienceVol. 12(48)
Department of Health (CN), Ministry of Education of the People's Republic of China (CN), Chinese University of Hong Kong (HK), Baylor College of Medicine (US), Neurosciences Institute (US), Hong Kong Science and Technology Parks Corporation (HK), Education University of Hong Kong (HK), Advanced Materials Enterprises (China) (CN), HKUST Shenzhen Research Institute (CN), Chinese University of Hong Kong, Shenzhen (CN), Hong Kong Biotechnology Organization (CN), Second Affiliated Hospital of Zhejiang University (CN), Qilu Hospital of Shandong University (CN), Baylor Genetics (US), Zhejiang University (CN), University of Hong Kong (HK)
Openalex Percentile: Top 76%
RNA modifications and cancer
DOIOpen Access PDFOpenAlex
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