Relevance to Autism

Li et al., 2023 reported 46 unrelated individuals with heterozygous missense or in-frame deletion variants in the U2AF2 gene, the majority of whom presented with developmental delay, intellectual disability, and facial dysmorphisms; autism or autistic features was reported in 11/25 (44%) of individuals in this cohort. Subsequent functional analysis in this report demonstrated that eight disease-associated U2AF2 missense variants dysregulated splicing of a model substrate, with two hyper-recurrent variants (p.Arg149Trp and p.Arg150Cys) being additionally shown to cause reduced neuritogenesis in neurons differentiated from human pluripotent stem cells, an impaired ability to rescue phenotypes in neural-specific U2af50 knockdown flies, and disruption of the Prp19 complex. A potentially deleterious de novo missense variant in the U2AF2 gene had previously been identified in an ASD proband from the SPARK cohort (Trost et al., 2022), and additional potentially deleterious missense variants in this gene have been observed in individuals with ASD or developmental delay (The Deciphering Developmental Disorders Study 2017; Wang et al., 2020).

Molecular Function

U2 auxiliary factor (U2AF), comprised of a large and a small subunit, is a non-snRNP protein required for the binding of U2 snRNP to the pre-mRNA branch site. This gene encodes the U2AF large subunit which contains a sequence-specific RNA-binding region with 3 RNA recognition motifs and an Arg/Ser-rich domain necessary for splicing. The large subunit binds to the polypyrimidine tract of introns early during spliceosome assembly. Heterozygous mutations in this gene are responsible for developmental delay, dysmorphic facies, and brain anomalies (DEVDFB; OMIM 620535), a disorder characterized by global developmental delay with impaired intellectual development, speech delay, nonspecific dysmorphic facial features, hypotonia, and impaired overall growth with small head circumference (Hiraide et al., 2021; Wang et al., 2023; Kittock et al., 2023; Kuroda et al., 2023).

External Links

References