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

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 <i>Fgf13</i> showed delayed neuronal migration during cortical development, and weakened learning and memory. Furthermore, this SNP reduced the interaction between <i>FGF13</i> 5'-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for <i>FGF13</i> translation in cortical neurons. Thus, this 5'-UTR SNP of <i>FGF13</i> interferes with the translational process of <i>FGF13</i> and causes deficits in brain development and cognitive functions.