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

Author:

Pan Xingyu12ORCID,Zhao Jingrong1,Zhou Zhiying3,Chen Jijun2,Yang Zhenxing3,Wu Yuxuan4,Bai Meizhu4,Jiao Yang5,Yang Yun6,Hu Xuye23,Cheng Tianling1,Lu Qianyun6,Wang Bin24,Li Chang-Lin23,Lu Ying-Jin23,Diao Lei4,Zhong Yan-Qing1,Pan Jing2,Zhu Jianmin3,Xiao Hua-Sheng3,Qiu Zi-Long1,Li Jinsong4ORCID,Wang Zefeng6,Hui Jingyi7,Bao Lan45ORCID,Zhang Xu12358ORCID

Affiliation:

1. Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

2. Shanghai Brain-Intelligence Project Center, Shanghai, China

3. Shanghai Clinical Center, Chinese Academy of Sciences/Xu-Hui Central Hospital, Shanghai, China

4. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

5. School of Life Science and Technology, Shanghai Tech University, Shanghai, China

6. CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai, China

7. State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

8. Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China

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.

Funder

National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Chinese Academy of Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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