SIK1 – Early Myoclonic Encephalopathy

Salt-inducible kinase 1 (SIK1) has been implicated in a severe developmental epilepsy, early myoclonic encephalopathy (MONDO:0016022), through heterozygous de novo mutations. SIK1 is a serine/threonine kinase involved in neuronal transcriptional regulation via HDAC5 phosphorylation, and its disruption leads to early-onset myoclonic seizures and neurodevelopmental impairment.

In a cohort of 101 infants with early myoclonic encephalopathy, six unrelated probands were found to harbor de novo SIK1 variants, including three truncating mutations and three missense changes outside the kinase domain (PMID:25839329). The identified variants comprise c.1840C>T (p.Gln614Ter), c.1897C>T (p.Gln633Ter), c.1039G>T (p.Glu347Ter), c.1231A>G (p.Ser411Gly), c.1906G>A (p.Gly636Ser), and c.860C>T (p.Pro287Leu), establishing autosomal dominant inheritance with recurrent de novo events.

No multigenerational segregation was observed, consistent with a de novo mechanism. Six probands with early myoclonic encephalopathy and SIK1 mutations support a strong genetic link without affected relatives (affected_relatives = 0).

Functional studies in patient-derived mutants demonstrated preserved autophosphorylation and HDAC5 kinase activity but revealed abnormal protein stability, mislocalization, and resistance to proteasomal degradation compared to wild-type SIK1, indicating a dominant-negative or gain-of-function effect on downstream transcriptional programs (PMID:25839329).

Further experiments in human cortical neurons showed that truncating SIK1 variants dysregulate MEF2C transcriptional activity, reduce expression of ARC, NR4A1, and NRG1, and alter neurite outgrowth and branching, linking SIK1 dysfunction to impaired synaptic activity response gene expression (PMID:27966542).

A CRISPR/Cas9 mouse model of C-terminal SIK1 truncation recapitulated excitatory/inhibitory synaptic imbalance, increased neuronal excitability, and autistic-like repetitive behaviors. Risperidone administration ameliorated excitatory transmission and behavioral phenotypes, underscoring potential therapeutic avenues (PMID:34295222).

Key Take-home: De novo SIK1 mutations cause autosomal dominant early myoclonic encephalopathy via dominant-negative effects on neuronal transcription and synapse function, supporting both diagnostic sequencing and exploration of synaptic modulators as targeted therapies.

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

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