Recurrent de novo MAPK8IP3 variants cause neurological phenotypes

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.