Related Experiment Video
Updated: Jan 26, 2026
A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
Recurrent de novo MAPK8IP3 variants cause neurological phenotypes
Shinya Iwasawa1, Kumiko Yanagi2, Atsuo Kikuchi1
1Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
Abstract:
c-Jun-amino-terminal kinase-interacting protein 3 (JIP3), encoded by MAPK8IP3, is an adaptor protein of the kinesin-1 complex and essential for axonal transport in neurons. However, an association between MAPK8IP3 variants and human disease has not been established. We identified 5 individuals from four families with recurrent de novo variants c.1732C>T (p.Arg578Cys) and c.3436C>T (p.Arg1146Cys) in MAPK8IP3. The core phenotype includes spastic diplegia, intellectual disability, cerebral atrophy, and corpus callosum hypoplasia. Zebrafish embryos overexpressing human mutant JIP3 showed axon varicosities of the posterior lateral line nerve, suggesting an adverse effect on the developing axons. Our results suggest that MAPK8IP3 variants cause a neurodevelopmental disease. ANN NEUROL 2019;85:927-933.
Insights
New variants in the MAPK8IP3 gene, encoding JIP3 (c-Jun-amino-terminal kinase-interacting protein 3), are linked to a novel neurodevelopmental disorder characterized by intellectual disability and spastic diplegia.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- c-Jun-amino-terminal kinase-interacting protein 3 (JIP3), encoded by MAPK8IP3, is crucial for axonal transport in neurons.
- The role of MAPK8IP3 variants in human disease remained unestablished prior to this study.
Purpose of the Study:
- To investigate the association between MAPK8IP3 variants and human disease.
- To characterize the clinical phenotype and underlying mechanisms of a potential MAPK8IP3-related neurodevelopmental disorder.
Main Methods:
- Identification and genetic analysis of individuals with recurrent de novo variants in MAPK8IP3.
- Clinical phenotyping of affected individuals, including neurological assessments and neuroimaging.
- Functional studies in zebrafish embryos to assess the impact of mutant JIP3 on axonal development.
Main Results:
- Five individuals from four families presented with recurrent de novo variants (c.1732C>T and c.3436C>T) in MAPK8IP3.
- The core clinical phenotype included spastic diplegia, intellectual disability, cerebral atrophy, and corpus callosum hypoplasia.
- Zebrafish embryos overexpressing human mutant JIP3 exhibited axon varicosities, indicating impaired axonal transport.
Conclusions:
- Recurrent de novo variants in MAPK8IP3 are associated with a novel neurodevelopmental disease.
- MAPK8IP3 variants disrupt axonal transport, contributing to the observed neurological deficits.
- This study establishes MAPK8IP3 as a disease-causing gene for a specific neurodevelopmental disorder.
Related Concept Videos
02:30Histone Variants at the Centromere
02:27Background and Environment Affect Phenotype
An example of how genetic background affects phenotype can be seen in horses. The Extension gene in horses is responsible for their coat color. A wild-type gene (EE) produces black pigment in the coat, while a mutant gene (ee) produces red pigment. A...
03:17Inheritance of Chromatin Structures
01:39Epistasis
02:39Gene Flow
01:57Protein Complexes with Interchangeable Parts
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...