BackgroundMutation in the UPF3B gene on chromosome X is implicated in neurodevelopmental disorders including X-linked intellectual disability, autism and schizophrenia. The protein UPF3B is involved in the nonsense-mediated mRNA decay pathway (NMD) that controls mRNA stability and functions in the prevention of the synthesis of truncated proteins.ResultsHere we show that NMD pathway components UPF3B and UPF1 are down-regulated during differentiation of neural stem cells into neurons. Using tethered function assays we found that UPF3B missense mutations described in families with neurodevelopmental disorders reduced the activity of UPF3B protein in NMD. In neural stem cells, UPF3B protein was detected in the cytoplasm and in the nucleus. Similarly in neurons, UPF3B protein was detected in neurites, the somatic cytoplasm and in the nucleus. In both cell types nuclear UPF3B protein was enriched in the nucleolus. Using GFP tagged UPF3B proteins we found that the missense mutations did not affect the cellular localisation. Expression of missense mutant UPF3B disturbed neuronal differentiation and reduced the complexity of the branching of neurites. Neuronal differentiation was similarly affected in the presence of the NMD inhibitor Amlexanox. The expression of mutant UPF3B proteins lead to a subtle increase in mRNA levels of selected NMD targets.ConclusionsTogether our findings indicate that, despite the down-regulation of NMD factors, functional NMD is critical for neuronal differentiation. We propose that the neurodevelopmental phenotype of UPF3B missense mutation is caused by impairment of NMD function altering neuronal differentiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0122-1) contains supplementary material, which is available to authorized users.

NLGN4X), neuroligin 3 (NLGN3) and SHANK3 genes [8][9][10]. The study of genetic factors associated with synaptic maturation is very important because the outcome from neuroimaging studies on autistic subjects demonstrates a defect in structural and functional brain connectivity [11].At this point, autism could be caused by defects at a genetic level which includes all the susceptible genes, leading to dysfunction at protein synthesis level. This could lead to abnormal synaptic structure and function, which affects ASD core regions of the brain, causing atypical neural system in the whole brain.