Relevance to Autism

In a report describing 32 individuals with pathogenic or likely pathogenic MAPK8IP3 variants recruited through the Cure MAPK8IP3 Foundation, Sudnawa et al., 2025 found that, in addition to phenotypes frequently associated with neurodevelopmental disorder with or without variable brain abnormalities (NEDBA; OMIM 618443), autism was observed in 31.3% of individuals in this cohort. Previous reports describing individuals with NEDBA found a diagnosis of autism spectrum disorder in 2/13 patients in Platzer et al., 2019 and autistic behavior in 2/5 patients in Iwasawa et al., 2019; both reports also demonstrated functional effects of patient-associated MAPK8IP3 variants in C. elegans and zebrafish. A number of de novo missense variants in the MAPK8IP3 gene have been reported in ASD probands, including a p.Tyr94Cys variant originally identified in an SSC proband that was experimentally shown to result in an adverse locomotion phenotype in C. elegans in Platzer et al., 2019 (Iossifov et al., 2014; Yuen et al., 2017; Zhou et al., 2022; Trost et al., 2022), while a de novo MAPK8IP3 nonsense variant was identified in a Chinese ASD proband in Wang et al., 2023.

Molecular Function

The protein encoded by this gene shares similarity with the product of Drosophila syd gene, required for the functional interaction of kinesin I with axonal cargo. Studies of the similar gene in mouse suggested that this protein may interact with, and regulate the activity of numerous protein kinases of the JNK signaling pathway, and thus function as a scaffold protein in neuronal cells. The C. elegans counterpart of this gene is found to regulate synaptic vesicle transport possibly by integrating JNK signaling and kinesin-1 transport.

External Links

References