Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• SIK1 syndrome is a rare developmental epilepsy disorder.
• It is caused by heterozygous mutations in the salt-inducible kinase 1 (SIK1) gene.
• The underlying molecular mechanisms of SIK1 syndrome remain largely unknown.

Purpose of the Study:

• To investigate the pathophysiological effects of SIK1 pathogenic sequence variations in human neurons.
• To elucidate the impact of SIK1 mutations on downstream gene targets and neuronal morphology.
• To explore the role of the MEF2C-ARC pathway in SIK1 syndrome pathogenesis.

Main Methods:

• Primary human fetal cortical neurons were utilized.
• Lentiviral vectors were employed to overexpress wild-type and mutant SIK1 protein.
• Transcriptional activity of downstream gene targets and neuronal morphology (neurite length, number, branching) were assessed.

Main Results:

• Truncating SIK1 variations led to abnormal MEF2C transcriptional activity and reduced MEF2C protein levels.
• Epilepsy-associated SIK1 variations significantly decreased the expression of ARC and other synaptic activity response element genes.
• The missense SIK1 variation p.(Pro287Thr) resulted in abnormal neuronal morphology, including reduced neurite length and number, and increased branching.

Conclusions:

• Epilepsy-causing SIK1 variations disrupt the MEF2C-ARC pathway, affecting neuronal development and synapse activity.
• This research provides initial insights into the pathogenesis of SIK1 syndrome.
• The findings extend the understanding of the ARX-MEF2C pathway's role in developmental epilepsy.