In XPO1, rs6735330 was associated with autism in all four cohorts (P<0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P(FDR))=1.29 x 10(-5)), the AGRE cohort (P(FDR)=0.0011) and the combined families (P(FDR)=2.34 x 10(-9)). These results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region. van Oirsouw et al., 2025 collected the clinical data of 22 individuals with de novo XPO1 variants [11 individuals with putative loss-of-function variants and 11 with coding variants (10 missense variants and one in-frame deletion variant)] through online matchmaking and identified an overlapping phenotype consistent with a monogenic neurodevelopmental disorder characterized by developmental delay and/or intellectual disability, microcephaly, structural brain abnormalities, behavioral problems, dysmorphic features, and different organ anomalies; 5/11 individuals with a missense or in-frame deletion variant in XPO1 were reported to have autism spectrum disorder, compared to only 1/11 individuals with a putative loss-of-function variant (45% vs. 9%). Additional functional studies of XPO1 in Drosophila in van Oirsouw et al., 2025 demonstrated that GABAergic neuron-specific knockdown flies demonstrated impaired habituation. A total of six de novo missense variants in XPO1 (five of which had a MPC >2) were previously identified in five ASD probands from the Autism Sequencing Consortium, the SPARK cohort, and the Simons Simplex Collection (Satterstrom et al., 2020; Zhou et al., 2022; Fu et al., 2022).
Molecular Function
The protein encoded by this gene mediates leucine-rich nuclear export signal (NES)-dependent protein transport. Exportin 1 specifically inhibits the nuclear export of Rev and U snRNAs. It is involved in the control of several cellular processes by controlling the localization of cyclin B, MPAK, and MAPKAP kinase 2. This protein also regulates NFAT and AP-1.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
2p15-p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders.
