biostudies-literatureZhang WTarget ALSThe Conrad Prebys Foundatione187199https://www.ebi.ac.uk/biostudies/studies/S-EPMC12016931biostudies-literatureUnknown10(8)Mitogen-activated protein kinase 8 interacting protein 3 (MAPK8IP3) gene encoding a protein called JIP3 is an adaption protein of the kinesin-1 complex known to play a role in axonal transport of cargo. Mutations in the gene have been linked to severe neurodevelopmental disorders, resulting in developmental delay, intellectual disability, ataxia, tremor, autism, seizures, and visual impairment. A patient who has a missense mutation in the MAPK8IP3 gene (c. 1714 C>T, Arg578Cys) (R578C) manifests dystonia, gross motor delay, and developmental delay. Here, we showed that the mutation was a toxic gain-of-function mutation that altered the interactome of JIP3; disrupted axonal transport of late endosomes; increased signaling via c-Jun N-terminal kinase, resulting in apoptosis; and disrupted dopJCI insightA toxic gain-of-function variant in MAPK8IP3 provides insights into JIP3 cellular roles.PMC12016931465TT-2024-C1-L1Zhang WChung WKMittal SThomas RForoughishafiei ACrooke STSkourti-Stathaki KNunes Bastos RfalseA toxic gain-of-function variant in MAPK8IP3 provides insights into JIP3 cellular roles.Mitogen-activated protein kinase 8 interacting protein 3 (MAPK8IP3) gene encoding a protein called JIP3 is an adaption protein of the kinesin-1 complex known to play a role in axonal transport of cargo. Mutations in the gene have been linked to severe neurodevelopmental disorders, resulting in developmental delay, intellectual disability, ataxia, tremor, autism, seizures, and visual impairment. A patient who has a missense mutation in the MAPK8IP3 gene (c. 1714 C>T, Arg578Cys) (R578C) manifests dystonia, gross motor delay, and developmental delay. Here, we showed that the mutation was a toxic gain-of-function mutation that altered the interactome of JIP3; disrupted axonal transport of late endosomes; increased signaling via c-Jun N-terminal kinase, resulting in apoptosis; and disrupted dop2025-01-01T00:00:00Z2025 Apr2026-06-03T04:52:52.52Z2026-05-28T03:06:54.739ZS-EPMC120169314011141210.1172/jci.insight.187199