Mutations in the spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• The spliceosome is crucial for gene expression via pre-mRNA splicing.
• Mutations in spliceosome components are linked to neurodevelopmental disorders, including primary microcephaly.

Purpose of the Study:

• To investigate the role of the spliceosomal protein SNW1 in splicing integrity and neurodevelopment.
• To elucidate the molecular mechanisms underlying SNW1 mutations in primary microcephaly.

Main Methods:

• Identified SNW1 mutations in patients with primary microcephaly.
• Utilized Drosophila and human cerebral organoid models to study SNW1 function.
• Performed RNA-sequencing to analyze splicing patterns and gene expression.

Main Results:

• Nine heterozygous SNW1 mutations impaired protein interactions and RNA splicing.
• SNW1 depletion reduced neural stem cell proliferation and increased apoptosis in model systems.
• Disrupted alternative splicing and altered expression of key neurodevelopment genes were observed.

Conclusions:

• SNW1 dysfunction contributes to primary microcephaly through defective splicing and impaired neurodevelopment.
• Proper spliceosome function, particularly SNW1, is vital for brain development.