Loss-of-function variants in MARK2 cause neurodevelopmental disorder.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Microtubule-affinity regulating kinase 2 (MARK2) is crucial for microtubule dynamics and neuronal polarity.
• Rare MARK2 variants have been associated with autism spectrum disorder (ASD) and neurodevelopmental delay (NDD).
• The functional impact of patient-derived MARK2 variants remains largely unknown.

Purpose of the Study:

• To investigate the functional consequences of NDD-linked MARK2 variants.
• To establish and utilize a humanized Drosophila model for variant interpretation.
• To propose a classification system for MARK2 variants based on functional effects.

Main Methods:

• Established a humanized Drosophila model expressing human MARK2.
• Systematically evaluated eight NDD-linked MARK2 variants using tissue-specific expression assays.
• Assessed variant effects on protein levels, viability, and wing patterning in Drosophila.

Main Results:

• MARK2 variants exhibited a spectrum of functional consequences, primarily hypomorphic or loss-of-function.
• Truncating variants led to reduced protein levels and loss-of-function.
• Most missense variants resulted in partial loss-of-function, while one variant (p.Lys224Glu) showed no pathogenicity in flies.
• Proposed a classification: not pathogenic, hypomorphic, and loss-of-function variants.

Conclusions:

• Drosophila serves as a valuable, scalable in vivo platform for interpreting the pathogenicity of NDD-linked variants.
• Reduced MARK2 activity is a potential mechanism contributing to neurodevelopmental disorders.
• Functional classification of MARK2 variants aids in understanding their role in NDD.