5'-UTR SNP of FGF13 causes translational defect and intellectual disability
Xingyu Pan, Jingrong Zhao, Zhiying Zhou, Ji‐Jun Chen, Zhenxing Yang, Yuxuan Wu, Meizhu Bai, Yang Jiao, Yun Yang, Xuye Hu, Tianling Cheng, Qianyun Lu, Bin Wang, Changlin Li, Ying‐Jin Lu, Lei Diao, Yanqing Zhong, Jing Pan, Jianmin Zhu, Huasheng Xiao, Zilong Qiu, Jinsong Li, Zefeng Wang, Jingyi Hui, Lan Bao, Xu Zhang
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.