SLK is mutated in individuals with a neurodevelopmental disorder

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Neuronal development relies on proper cytoskeletal organization.
• Ste20-like kinase (SLK) is implicated in cytoskeletal regulation and microtubule polarity.
• Previous research linked SLK deficiency to defects in murine cortical development, but not human neurodevelopmental disorders.

Purpose of the Study:

• To investigate the role of SLK in human neurodevelopmental disorders.
• To identify genetic variants in SLK associated with neurodevelopmental conditions.
• To elucidate the cellular mechanisms underlying SLK-related neurodevelopmental phenotypes.

Main Methods:

• Clinical phenotyping of affected individuals and families.
• Positional mapping and exome sequencing to identify genetic variants.
• Functional studies using patient-derived cells, SLK knockdown models, and a Drosophila orthologue model.

Main Results:

• Three individuals from three families presented with biallelic SLK variants and a neurodevelopmental disorder.
• Patient-derived cells exhibited abnormal cytoskeleton organization, impaired migration, and polarization.
• Transdifferentiated neurons showed immature morphology with reduced dendritic arborization.
• Drosophila models confirmed the deleterious effects of Slik deficiency on synapse maturation and locomotion.

Conclusions:

• Results support an autosomal recessive SLK-related neurodevelopmental disorder.
• Abnormal cytoskeleton-mediated neuronal maturation is the proposed underlying mechanism.
• SLK is identified as a novel gene associated with human neurodevelopmental disorders.