Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Exportin 1 (XPO1) is essential for nucleo-cytoplasmic transport and mitosis.
• XPO1 gene deletions are observed in 2p15p16.1 microdeletion syndrome.
• No monogenic disorder linked to XPO1 had been previously described.

Purpose of the Study:

• To investigate the role of XPO1 in monogenic disorders.
• To characterize the phenotype associated with de novo XPO1 variants.
• To explore XPO1 function in development and learning.

Main Methods:

• Collected clinical data from 22 individuals with de novo XPO1 variants.
• Utilized Drosophila melanogaster as a model organism to study XPO1 function.
• Performed ubiquitous and neuron-specific knockdown experiments in Drosophila.

Main Results:

• Identified an overlapping phenotype in individuals with XPO1 variants, consistent with a neurodevelopmental disorder (NDD).
• Demonstrated that XPO1 is critical for development in Drosophila.
• Showed that knockdown of XPO1 in GABAergic neurons impairs habituation learning in flies.

Conclusions:

• XPO1 is established as a novel gene responsible for a dominant monogenic NDD.
• XPO1 plays a fundamental role in neurodevelopment and learning processes.