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MED12 -Related Disease in a Chinese Girl: Clinical Characteristics and Underlying Mechanism

  • Wang, Chao1
  • Lin, Longlong1
  • Xue, Yan2
  • Wang, Yilin1
  • Liu, Zhao3
  • Ou, Zicheng4
  • Wu, Shengnan1
  • Lan, Xiaoping1
  • Zhang, Yuanfeng1
  • Yuan, Fang1
  • Luo, Xiaona1
  • Wang, Chunmei1
  • Xi, Jiaming1
  • Sun, Xiaomin1
  • Chen, Yucai1
  • 1 Department of Neurology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai , (China)
  • 2 Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai , (China)
  • 3 Division of Pediatric Neurology, Department of Pediatrics, University of Illinois and Children's Hospital of Illinois, Peoria, IL , (United States)
  • 4 Department of Pediatrics, JianNing General Hospital, Fujian , (China)
Published Article
Frontiers in Genetics
Frontiers Media SA
Publication Date
Feb 27, 2020
DOI: 10.3389/fgene.2020.00129
PMID: 32174975
PMCID: PMC7056888
PubMed Central
  • Genetics
  • Brief Research Report


The RNA polymerase II transcription subunit 12 homolog ( MED12 ) is a member of the mediator complex, which plays a critical role in RNA transcription. Mutations in MED12 cause X-linked intellectual disability and other anomalies collectively grouped as MED12 -related disorders. While MED12 mutations have been most commonly reported in male patients, we present the case of a 1-year-old girl with clinical characteristics similar to MED12- related disorders. To explore the clinical characteristics of the condition and its possible pathogenesis, we analyzed the patient’s clinical data; genetic testing by whole-exome sequencing revealed a de novo heterozygous mutation (c.1249-1G > C) in MED12 . Further cDNA experiments revealed that the patient had an abnormal splicing at the skipping of exon9, which may have produced a truncated protein. qPCR showed decreased MED12 gene expression level in the patient, and an X-chromosome inactivation test confirmed a skewed inactivation of the X-chromosome. The lymphoblast transcription levels of the genes involved in the Gli3-dependent sonic hedgehog (SHH) signaling pathway, namely, CREB5, BMP4 , and NEUROG2 , were found to be significantly elevated compared with those of her parents and sex- and age-matched controls. Our results support the view that MED12 mutations may dysregulate the SHH signaling pathway, which may have accounted for the aberrant craniofacial morphology of our patient.

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