Poster Presentation 47th Lorne Genome Conference 2026

UPF1 variants cause intellectual disability via mechanisms convergent with fragile X syndrome and P-body dysfunction   (133459)

Lachlan A Jolly 1 , Natalie Tan 2 , Urwah Nawaz 1 , Saba Montazaribarforoushi 1 , Valeriya Gyurkovska 3 , Michael Silk 4 , Lachlan Baer 1 , Emmylou Nicolas-Martinez 1 , John Christodoulou 2 , Nava Segev 3 , Sue White 2 , Jozef Gecz 1
  1. Robinson Research Institute, The University of Adelaide, Adelaide, S.A., Australia
  2. Murdoch Children’s Research Institute, Melbourne, Vic, Australia
  3. Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL, USA
  4. Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, N.S.W., Australia

UPF1 encodes an ATP-dependent RNA helicase that functions in several mRNA decay pathways, most notably the translation-dependent nonsense mediated mRNA decay (NMD) pathway. We now identified 24 individuals with ID harbouring de novo heterozygous UPF1 missense variants. Variants were predicted to be deleterious to function and were clustered in regions which impact RNA and/or ATP binding. While RNA sequencing revealed that 5% of the transcriptome was deregulated in UPF1 variant cells, NMD itself was not overtly affected. We investigated an alternative mechanism involving the mRNA binding protein FMR1, which functions as a translational inhibitor and whose loss-of-function causes Fragile X, the leading monogenetic cause of ID in males.  Using immunoprecipitation and proximity-ligation assays, we confirm UPF1 interacts with FMR1 endogenously within cytoplasmic P-body-like puncta, and that the UPF1-FMR1 interaction was disrupted in UPF1 variant cells. Reciprocally, we show increased UPF1 phosphorylation in Fragile X cells. Remarkably, we discovered the differentially expressed genes (DEGs) identified in UPF1 variant cells significantly overlapped (32%, p=9.8x10-61) and correlated (R=0.95; p=2.2x10-16) with those identified in Fragile X cells. This shared impact was also observed at the level of the proteome. Further investigations revealed downregulated mRNAs had low-GC content, indicating a possible involvement of defective mRNA processing and storage within P-bodies. Immunoprecipitation coupled proteomics found proteins differentially bound to variant UPF1 were 3.2-fold enriched for P-bodies components (p< 7.4x10-07). Finally, we show a >25% reduction in the number of P-bodies in both UPF1 variants and Fragile X cells, which were also unusually resistant to dissolution using the solvent 1,6-hexanediol. In summary, we define a novel UPF1-related syndromic ID, with transcriptome and proteome impacts shared with Fragile X syndrome, suggesting a convergent pathogenic mechanism involving the co-regulation of mRNAs in P-bodies by UPF1 and FMRP.