eLife (Jun 2021)

5'-UTR SNP of FGF13 causes translational defect and intellectual disability

  • Xingyu Pan,
  • Jingrong Zhao,
  • Zhiying Zhou,
  • Jijun Chen,
  • Zhenxing Yang,
  • Yuxuan Wu,
  • Meizhu Bai,
  • Yang Jiao,
  • Yun Yang,
  • Xuye Hu,
  • Tianling Cheng,
  • Qianyun Lu,
  • Bin Wang,
  • Chang-Lin Li,
  • Ying-Jin Lu,
  • Lei Diao,
  • Yan-Qing Zhong,
  • Jing Pan,
  • Jianmin Zhu,
  • Hua-Sheng Xiao,
  • Zi-Long Qiu,
  • Jinsong Li,
  • Zefeng Wang,
  • Jingyi Hui,
  • Lan Bao,
  • Xu Zhang

DOI
https://doi.org/10.7554/eLife.63021
Journal volume & issue
Vol. 10

Abstract

Read online

The congenital intellectual disability (ID)-causing gene mutations remain largely unclear, although many genetic variations might relate to ID. We screened gene mutations in Chinese Han children suffering from severe ID and found a single-nucleotide polymorphism (SNP) in the 5′-untranslated region (5′-UTR) of fibroblast growth factor 13 (FGF13) mRNA (NM_001139500.1:c.-32c>G) shared by three male children. In both HEK293 cells and patient-derived induced pluripotent stem cells, this SNP reduced the translation of FGF13, which stabilizes microtubules in developing neurons. Mice carrying the homologous point mutation in 5′-UTR of Fgf13 showed delayed neuronal migration during cortical development, and weakened learning and memory. Furthermore, this SNP reduced the interaction between FGF13 5′-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for FGF13 translation in cortical neurons. Thus, this 5′-UTR SNP of FGF13 interferes with the translational process of FGF13 and causes deficits in brain development and cognitive functions.

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