Human Genetics

, Volume 133, Issue 6, pp 801–811 | Cite as

A novel variant in the 3′ UTR of human SCN1A gene from a patient with Dravet syndrome decreases mRNA stability mediated by GAPDH’s binding

  • Tao Zeng
  • Zhao-Fei Dong
  • Shu-Jing Liu
  • Rui-Ping Wan
  • Ling-Jia Tang
  • Ting Liu
  • Qi-Hua Zhao
  • Yi-Wu Shi
  • Yong-Hong Yi
  • Wei-Ping Liao
  • Yue-Sheng LongEmail author
Original Investigation


Mutations in the SCN1A gene-encoding voltage-gated sodium channel α-I subunit (Nav1.1) cause various spectrum of epilepsies including Dravet syndrome (DS), a severe and intractable form. A large number of SCN1A mutations identified from the DS patients lead to the loss of function or truncation of Nav1.1 that result in a haploinsufficiency effects, indicating that the exact expression level of SCN1A should be essential to maintain normal brain function. In this study, we have identified five variants c.*1025T>C, c.*1031A>T, c.*1739C>T, c.*1794C>T and c.*1961C>T in the SCN1A 3′ UTR in the patients with DS. The c.*1025T>C, c.*1031A>T and c.*1794C>T are conserved among different species. Of all the five variants, only c.*1794C>T is a novel variant and alters the predicted secondary structure of the 3′ UTR. We also show that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) only binds to the 3′ UTR sequence containing the mutation allele 1794U but not the wild-type allele 1794C, indicating that the mutation allele forms a new GAPDH-binding site. Functional analyses show that the variant negatively regulates the reporter gene expression by affecting the mRNA stability that is mediated by GAPDH’s binding, and this phenomenon could be reversed by shRNA-induced GAPDH knockdown. These findings suggest that GAPDH and the 3′-UTR variant are involved in regulating SCN1A expression at post-transcriptional level, which may provide an important clue for further investigating on the relationship between 3′-UTR variants and SCN1A-related diseases.


mRNA Stability Ketogenic Diet Reporter Gene Expression Mutation Construct SCN1A Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank all the subjects and their families for their help with this work. We are grateful to the He Shanheng Charity Foundation for contributing to the development of this institute. This work was supported by the National Natural Science Foundation of China (Grant Number 31070928 and 81371436 to Y.S.L., 81271434 to W.P.L., 81171073 to Y.H.Y. and 81071045 to Y.W.S.), the Guangzhou Scholar Project (Grant Number 10A011G to Y.S.L.) and the Scientific Research of Guangzhou Municipal Colleges and Universities (Grant Number 10A211 to Y.S.L.).

Conflict of interest

None declared.

Supplementary material

439_2014_1422_MOESM1_ESM.pdf (236 kb)
Supplementary material 1 (PDF 235 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Tao Zeng
    • 1
  • Zhao-Fei Dong
    • 1
  • Shu-Jing Liu
    • 1
  • Rui-Ping Wan
    • 1
  • Ling-Jia Tang
    • 1
  • Ting Liu
    • 1
  • Qi-Hua Zhao
    • 1
  • Yi-Wu Shi
    • 1
  • Yong-Hong Yi
    • 1
  • Wei-Ping Liao
    • 1
  • Yue-Sheng Long
    • 1
    Email author
  1. 1.Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of ChinaInstitute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina

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