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

Elife. 2021 Jun 29:10:e63021. doi: 10.7554/eLife.63021.

Abstract

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.

Keywords: 5'-untranslated region; Intellectual disability; fibroblast growth factor 13; human; mouse; neuroscience; polypyrimidine-tract-binding protein 2; protein translation; single-nucleotide polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics*
  • Adolescent
  • Animals
  • Child
  • Child, Preschool
  • Fibroblast Growth Factors / genetics*
  • Fibroblast Growth Factors / metabolism
  • HEK293 Cells
  • Humans
  • Intellectual Disability / genetics*
  • Learning
  • Male
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Point Mutation*
  • Polymorphism, Single Nucleotide*

Substances

  • 5' Untranslated Regions
  • fibroblast growth factor 13
  • Fibroblast Growth Factors