biostudies-literatureYokoi SMEXT | Japan Society for the Promotion of ScienceJapan Agency for Medical Research and Development8881-8896https://www.ebi.ac.uk/biostudies/studies/S-EPMC9698725biostudies-literatureUnknown42(47)Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (<i>Syngap1</i>) mRNA at its 3' untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the <i>SYNGAP1</i> 3'UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the <i>SYNGAP1</i> variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the <i>SYNGAP1</i> variant excessively recruiThe Journal of neuroscience : the official journal of the Society for NeuroscienceThe <i>SYNGAP1</i> 3'UTR Variant in ALS Patients Causes Aberrant <i>SYNGAP1</i> Splicing and Dendritic Spine Loss by Recruiting HNRNPK.PMC9698725JP21ek0109434JP20K16489Izumi YKano ONakatochi MIto TOkano HMorita MSahashi KYokoi SOda MAtsuta NOkada YIshigaki SUdagawa TSone TSobue GTohnai GNakamura RKatsuno MFujioka YfalseThe <i>SYNGAP1</i> 3'UTR Variant in ALS Patients Causes Aberrant <i>SYNGAP1</i> Splicing and Dendritic Spine Loss by Recruiting HNRNPK.Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (<i>Syngap1</i>) mRNA at its 3' untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the <i>SYNGAP1</i> 3'UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the <i>SYNGAP1</i> variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the <i>SYNGAP1</i> variant excessively recrui2022-01-01T00:00:00Z2022 Nov2026-06-21T03:14:22.706Z2025-04-19T22:46:09.471ZS-EPMC96987253626128310.1523/JNEUROSCI.0455-22.2022