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

Abstract

SIK1 syndrome is a newly described developmental epilepsy disorder caused by heterozygous mutations in the salt-inducible kinase SIK1. To better understand the pathophysiology of SIK1 syndrome, we studied the effects of SIK1 pathogenic sequence variations in human neurons. Primary human fetal cortical neurons were transfected with a lentiviral vector to overexpress wild-type and mutant SIK1 protein. We evaluated the transcriptional activity of known downstream gene targets in neurons expressing mutant SIK1 compared with wild type. We then assayed neuronal morphology by measuring neurite length, number and branching. Truncating SIK1 sequence variations were associated with abnormal MEF2C transcriptional activity and decreased MEF2C protein levels. Epilepsy-causing SIK1 sequence variations were associated with significantly decreased expression of ARC (activity-regulated cytoskeletal-associated) and other synaptic activity response element genes. Assay of mRNA levels for other MEF2C target genes NR4A1 (Nur77) and NRG1, found significantly, decreased the expression of these genes as well. The missense p.(Pro287Thr) SIK1 sequence variation was associated with abnormal neuronal morphology, with significant decreases in mean neurite length, mean number of neurites and a significant increase in proximal branches compared with wild type. Epilepsy-causing SIK1 sequence variations resulted in abnormalities in the MEF2C-ARC pathway of neuronal development and synapse activity response. This work provides the first insights into the mechanisms of pathogenesis in SIK1 syndrome, and extends the ARX-MEF2C pathway in the pathogenesis of developmental epilepsy.

Pure 21q22.3 deletion identified in a patient with mild phenotypic features

“…Heterozygous mutations in SIK1 gene were associated to epileptic encephalopathy probably caused by variant and truncated SIK1 proteins (Hansen et al ). Also, sequence variations in the SIK1 gene resulted in significant abnormalities of synapse regulation and neuronal morphology in in vitro human neuronal model, causing epilepsy in some cases (Proschel et al ), a feature described in the present case.…”

Nuts and bolts of the salt-inducible kinases (SIKs)

“…On the other hand, the truncation mutants all displayed increased stability and increased cytoplasmic localisation compared with wild-type SIK1 [ 102 ]. As a result of multiple SIK1 mutations being identified in patients, a new subset of developmental epilepsy has been identified and termed SIK1 syndrome [ 103 ].…”

Salt inducible kinases as novel Notch interactors in the developing Drosophila retina

“…Additionally, both Drosophila Sik2 and Sik3 were shown to interact with the Hippo pathway to regulate tissue growth and size [30]. Siks are also implicated in diseases such as diabetes [31], epilepsy [32], various cancer types [33][34][35][36] and cancer progression (reviewed in [37]). Given their proposed roles in mitotic mechanisms and response to starvation, Siks have been shown to be the molecular link between sugar metabolism, tumorigenesis and cancer progression [38,39].…”