ResearchIn-Press PreviewCell biologyGeneticsTherapeutics
Open Access | 10.1172/jci.insight.187199
1n-Lorem Foundation, Carlsbad, United States of America
2ONI Inc., San Diego, United States of America
3Boston Children’s Hospital, Harvard Medical School, Brookline, United States of America
Find articles by Zhang, W. in: JCI | PubMed | Google Scholar
1n-Lorem Foundation, Carlsbad, United States of America
2ONI Inc., San Diego, United States of America
3Boston Children’s Hospital, Harvard Medical School, Brookline, United States of America
Find articles by Mittal, S. in: JCI | PubMed | Google Scholar
1n-Lorem Foundation, Carlsbad, United States of America
2ONI Inc., San Diego, United States of America
3Boston Children’s Hospital, Harvard Medical School, Brookline, United States of America
Find articles by Thomas, R. in: JCI | PubMed | Google Scholar
1n-Lorem Foundation, Carlsbad, United States of America
2ONI Inc., San Diego, United States of America
3Boston Children’s Hospital, Harvard Medical School, Brookline, United States of America
Find articles by Foroughishafiei, A. in: JCI | PubMed | Google Scholar
1n-Lorem Foundation, Carlsbad, United States of America
2ONI Inc., San Diego, United States of America
3Boston Children’s Hospital, Harvard Medical School, Brookline, United States of America
Find articles by Nunes Bastos, R. in: JCI | PubMed | Google Scholar
1n-Lorem Foundation, Carlsbad, United States of America
2ONI Inc., San Diego, United States of America
3Boston Children’s Hospital, Harvard Medical School, Brookline, United States of America
Find articles by Chung, W. in: JCI | PubMed | Google Scholar
1n-Lorem Foundation, Carlsbad, United States of America
2ONI Inc., San Diego, United States of America
3Boston Children’s Hospital, Harvard Medical School, Brookline, United States of America
Find articles by Skourti-Stathaki, K. in: JCI | PubMed | Google Scholar
1n-Lorem Foundation, Carlsbad, United States of America
2ONI Inc., San Diego, United States of America
3Boston Children’s Hospital, Harvard Medical School, Brookline, United States of America
Find articles by Crooke, S. in: JCI | PubMed | Google Scholar
Published March 20, 2025 - More info
Mitogen-activated protein kinase 8 interacting protein 3 (MAPK8IP3/JIP3) is a member of the kinesin family 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 show that the mutation is a toxic gain of function mutation which alters the interactome of JIP3, disrupts axonal transport of late endosomes, increases signaling via c-Jun N-terminal kinase (JNK), resulting in apoptosis, and disrupts the dopamine receptor 1 (D1) signaling while not affecting the dopamine receptor 2 (D2) signaling. Further, in the presence of the mutant protein, we show that 80% reduction of mutant JIP3>80% and 60% reduction of wild-type JIP3 by non-allele selective phosphorothioate (PS)-modified antisense oligonucleotides (ASOs) is well tolerated by several types of cells in vitro. Our study identifies several important new roles for JIP3 and provides important insights for therapeutic approaches, including antisense oligonucleotide reduction of JIP3.