SIK1 – Developmental and Epileptic Encephalopathy

Salt-inducible kinase 1 (SIK1) has been implicated in autosomal dominant developmental and epileptic encephalopathy (developmental and epileptic encephalopathy). Affected individuals present with early-onset refractory seizures, epileptiform EEG abnormalities, and global developmental delay or regression.

Genetic evidence includes seven unrelated probands with heterozygous de novo SIK1 variants (6 truncating and 1 missense) identified in cohorts with Ohtahara syndrome, early myoclonic encephalopathy, and infantile spasms (PMID:25839329, PMID:35267137). The variant spectrum comprises LoF mutations (nonsense and frameshift) and missense changes clustering outside the kinase domain. One recurrent missense, c.880G>A (p.Ala294Thr), was reported in a pediatric case with mild DEE30 features (PMID:35267137). No multigenerational segregation has been observed.

Phenotypically, affected individuals exhibit infantile seizure onset, variable drug responsiveness, normal brain MRI in some cases, and a spectrum ranging from severe epileptic-dyskinetic encephalopathy to milder pediatric epilepsy. Developmental delay and regression are consistent across reports.

Functional studies demonstrate that truncating SIK1 mutants resist proteasomal degradation, mislocalize subcellularly, and retain aberrant kinase activity toward HDAC5, disrupting MEF2C transcriptional regulation (PMID:25839329). In primary human neurons, epilepsy-causing SIK1 variants reduce expression of MEF2C target genes including ARC, NRG1, and NR4A1, and impair neuronal morphology with decreased neurite length and branching (PMID:27966542).

A SIK1 C-terminal truncation mouse model recapitulates excitatory/inhibitory synaptic imbalance, enhanced pyramidal neuron excitability, and repetitive behaviors; risperidone attenuates excitatory transmission and behavioral phenotypes, confirming dominant-negative mechanism (PMID:34295222).

Collectively, de novo SIK1 mutations are strongly associated with developmental and epileptic encephalopathy via dominant-negative effects on MEF2C-mediated synaptic gene regulation. Additional roles of SIK1 in immunity exist but exceed current ClinGen scoring. Key Take-home: SIK1 testing informs diagnosis of DEE30 and guides functional interpretation for precision therapy.

References

• American journal of human genetics | 2015 | De novo mutations in SIK1 cause a spectrum of developmental epilepsies. PMID:25839329
• European journal of human genetics : EJHG | 2017 | Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology. PMID:27966542
• Frontiers in molecular neuroscience | 2021 | Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK1. PMID:34295222
• Metabolic brain disease | 2022 | Novel mutation of SIK1 gene causing a mild form of pediatric epilepsy in a Chinese patient. PMID:35267137

Evidence Based Scoring (AI generated)