Alternative titles; symbols
HGNC Approved Gene Symbol: SIK1
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38): 21:43,414,483-43,427,131 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Developmental and epileptic encephalopathy 30 | 616341 | Autosomal dominant | 3 |
The SIK1 gene encodes a member of the AMP kinase subfamily that plays a role in a signal transduction pathway involved in the nuclear regulation of gene expression (summary by Hansen et al., 2015).
In Drosophila and C. elegans, signal transduction pathways initiated by the activation of receptor-protein tyrosine kinases can mediate developmental fate decisions. To study whether similar mechanisms are used during mammalian embryogenesis, Ruiz et al. (1994) searched for protein kinases expressed during heart development in the mouse. Using an RT-PCR-based approach to amplify protein kinase-specific products from cDNAs obtained from heart tissues at 8.5 days postcoitum (dpc), they identified 2 novel PCR products. One, designated Hek2, encodes the mouse ortholog of human HEK2 (601839), a member of the eph receptor protein tyrosine kinase gene family. The other, designated msk (myocardial Snf1-like kinase), encodes a putative protein serine/threonine kinase most similar to the yeast protein Snf1, which is involved in the response to nutritional stress. Msk mRNA expression is restricted to myocardial cells and their progenitors in the 7.75- to 8.5-dpc developing heart. Subsequently, msk mRNA expression is rapidly downregulated.
Modification of histones is an important element in the regulation of gene expression. Lo et al. (2001) purified a histone H3 (see 142780) serine-10 kinase complex from S. cerevisiae and identified its catalytic subunit as Snf1. The SNF1/AMPK family of kinases function in conserved signal transduction pathways. Lo et al. (2001) showed that Snf1 and the acetyltransferase Gcn5 (602301) function in an obligate sequence to enhance Ino1 transcription by modifying histone H3 serine-10 and lysine-14. Thus, phosphorylation and acetylation are targeted to the same histone by promoter-specific regulation by a kinase/acetyltransferase pair, supporting models of gene regulation wherein transcription is controlled by coordinated patterns of histone modification.
Stephenson et al. (2004) found that Chinese hamster ovary cells expressing an inducible human SNF1LK kinase domain did not divide, but underwent additional rounds of replication to yield 8N and 16N cells. These findings suggested a role for SNF1LK in G2/M regulation.
Berdeaux et al. (2007) found that transgenic mice expressing a dominant-negative form of Creb (123810) (A-Creb) in muscle exhibited a dystrophic phenotype accompanied by extensive fiber necrosis and reduced Mef2 (see 600660) activity. Class II HDAC (see HDAC5; 605315) phosphorylation was decreased in A-Creb myofibers due to a reduction in the levels of Sik1, a Creb target gene that functions as a class II HDAC kinase. Inhibition of class II HDAC activity via expression of Sik1 or a small molecule inhibitor ameliorated the dystrophic phenotype of mice expressing A-Creb in muscle, suggesting that the SIK1-HDAC pathway has a role in regulating muscle function.
Physiologic increases in intracellular sodium concentration are associated with parallel increases in activity of the sodium/potassium ATPase (see ATP1A1; 182310) at the plasma membrane. Sjostrom et al. (2007) found that increased intracellular sodium in intact mammalian cells triggered sodium-dependent activation of an intracellular signaling network with SIK1 at its core. SIK1 was activated by phosphorylation on thr322, and activation of SIK1 resulted in dephosphorylation of the sodium/potassium ATPase alpha subunit, increasing its catalytic activity.
By sequence analysis, Hattori et al. (2000) mapped the human SNF1LK gene to chromosome 21q22.3.
In 6 unrelated children with developmental and epileptic encephalopathy-30 (DEE30; 616341), Hansen et al. (2015) identified 6 different de novo heterozygous mutations, 3 missense and 3 truncating, in the SIK1 gene (see, e.g., 605705.0001-605705.0005). In vitro functional expression studies showed that all the mutant proteins identified, even the truncated ones, retained autophosphorylation activity as well as the ability to phosphorylate HDAC5 fragments. Studies in HEK293 cells showed that the missense mutant proteins had normal punctate nuclear localization, similar to wildtype, whereas the truncated proteins had a broader pattern of localization in the nucleus and cytoplasm as well as increased stability compared to wildtype.
Proschel et al. (2017) found that truncating DEE30-causing SIK1 mutations disrupted MEF2C (600662) transcription and protein expression. SIK1 mutations also decreased expression of ARC (612461) and other synaptic activity response element genes. However, SIK1 mutations did not affect the ability of SIK1 to phosphorylate HDAC5, nor did they affect TORC1 (CRTC1; 607536) or CREB1 protein levels or CREB1 transcriptional activity. In addition, SIK1 mutations were associated with abnormal neuronal morphology in human fetal neurons.
In a male infant (DB13-001) with developmental and epileptic encephalopathy-30 (DEE30; 616341), Hansen et al. (2015) identified a de novo heterozygous c.895C-A transversion (c.895C-A, NM_173354.3) in the SIK1 gene, resulting in a pro287-to-thr (P287T) substitution. The mutation, which was found by whole-exome sequencing, was not found in the Exome Variant Server (EVS6500) or Exome Aggregation Consortium databases. Studies in HEK293 cells showed that the P287T mutant protein had normal punctate nuclear localization, similar to wildtype. The patient developed myoclonic seizures in the first days of life and died at 10 months of age.
In a male infant (DB14-013) with developmental and epileptic encephalopathy-30 (DEE30; 616341), Hansen et al. (2015) identified a de novo heterozygous c.1039G-T transversion (c.1039G-T, NM_173354.3) in the SIK1 gene, resulting in a glu347-to-ter (E347X) substitution. The mutation was not found in the Exome Variant Server (EVS6500) or Exome Aggregation Consortium databases. Transfection of the mutation into HEK293 cells showed that the mutant truncated protein had increased stability compared to wildtype but also had a broader pattern of localization in the nucleus and cytoplasm. Postmortem brain tissue from the patient showed that the mutant truncated protein was predominant in the neuronal cytoplasm only, suggesting impaired nuclear localization. The patient developed myoclonic seizures soon after birth and died at 3 months of age.
In a 15-year-old girl (IS13-013) with developmental and epileptic encephalopathy-30 (DEE30; 616341), Hansen et al. (2015) identified a de novo heterozygous c.1840C-T transition (c.1840C-T, NM_173354.3) in the SIK1 gene, resulting in a gln614-to-ter (Q614X) substitution. The mutation was not found in the Exome Variant Server (EVS6500) or Exome Aggregation Consortium databases. Transfection of the mutation into HEK293 cells showed that the mutant truncated protein had increased stability compared to wildtype but also had a broader pattern of localization in the nucleus and cytoplasm. The patient developed infantile spasms at 4 months of age and showed severely impaired global development.
In an 8-year-old girl (IS09-018) with developmental and epileptic encephalopathy-30 (DEE30; 616341), Hansen et al. (2015) identified a de novo heterozygous c.1897C-T transition (c.1897C-T, NM_173354.3) in the SIK1 gene, resulting in a gln633-to-ter (Q633X) substitution. The mutation was not found in the Exome Variant Server (EVS6500) or Exome Aggregation Consortium databases. Transfection of the mutation into HEK293 cells showed that the mutant truncated protein had increased stability compared to wildtype but also had a broader pattern of localization in the nucleus and cytoplasm. The patient developed seizures at 2 months of age and had severely impaired global development with absent speech and inability to walk.
In a 10-year-old girl (LR05-086) with developmental and epileptic encephalopathy-30 (DEE30; 616341), Hansen et al. (2015) identified a de novo heterozygous c.1906G-A transition (c.1906G-A, NM_173354.3) in the SIK1 gene, resulting in a gly636-to-ser (G636S) substitution. The mutation was not found in the Exome Variant Server (EVS6500) or Exome Aggregation Consortium databases. Studies in HEK293 cells showed that the G636S mutant protein had normal punctate nuclear localization, similar to wildtype. The patient developed myoclonic jerks and tonic seizures soon after birth. EEG was consistent with Ohtahara syndrome. She had severely impaired development with absent speech and few spontaneous movements.
Berdeaux, R., Goebel, N., Banaszynski, L., Takemori, H., Wandless, T., Shelton, G. D., Montminy, M. SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nature Med. 13: 597-603, 2007. [PubMed: 17468767] [Full Text: https://doi.org/10.1038/nm1573]
Hansen, J., Snow, C., Tuttle, E., Ghoneim, D. H., Yang, C.-S., Spencer, A., Gunter, S. A., Smyser, C. D., Gurnett, C. A., Shinawi, M., Dobyns, W. B., Wheless, J., Halterman, M. W., Jansen, L. A., Paschal, B. M., Paciorkowski, A. R. De novo mutations in SIK1 cause a spectrum of developmental epilepsies. Am. J. Hum. Genet. 96: 682-690, 2015. Note: Erratum: Am. J. Hum. Genet. 96: 1009 only, 2015. [PubMed: 25839329] [Full Text: https://doi.org/10.1016/j.ajhg.2015.02.013]
Hattori, M., Fujiyama, A., Taylor, T. D., Watanabe, H., Yada, T., Park, H.-S., Toyoda, A., Ishii, K., Totoki, Y., Choi, D.-K., Groner, Y., Soeda, E., and 52 others. The DNA sequence of human chromosome 21. Nature 405: 311-319, 2000. Note: Erratum: Nature: 407: 110 only, 2000. [PubMed: 10830953] [Full Text: https://doi.org/10.1038/35012518]
Lo, W.-S., Duggan, L., Emre, N. C. T., Belotserkovskya, R., Lane, W. S., Shiekhattar, R., Berger, S. L. Snf1--a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science 293: 1142-1146, 2001. [PubMed: 11498592] [Full Text: https://doi.org/10.1126/science.1062322]
Proschel, C., Hansen, J. N., Ali, A., Tuttle, E., Lacagnina, M., Buscaglia, G., Halterman, M. W., Paciorkowski, A. R. Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology. Europ. J. Hum. Genet. 25: 216-221, 2017. [PubMed: 27966542] [Full Text: https://doi.org/10.1038/ejhg.2016.145]
Ruiz, J. C., Conlon, F. L., Robertson, E. J. Identification of novel protein kinases expressed in the myocardium of the developing mouse heart. Mech. Dev. 48: 153-164, 1994. [PubMed: 7893599] [Full Text: https://doi.org/10.1016/0925-4773(94)90056-6]
Sjostrom, M., Stenstrom, K., Eneling, K., Zwiller, J., Katz, A. I., Takemori, H., Bertorello, A. M. SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process. Proc. Nat. Acad. Sci. 104: 16922-16927, 2007. [PubMed: 17939993] [Full Text: https://doi.org/10.1073/pnas.0706838104]
Stephenson, A., Huang, G.-Y., Nguyen, N.-T., Reuter, S., McBride, J. L., Ruiz, J. C. snf1lk encodes a protein kinase that may function in cell cycle regulation. Genomics 83: 1105-1115, 2004. Note: Erratum: Genomics 85: 152 only, 2005. [PubMed: 15177563] [Full Text: https://doi.org/10.1016/j.ygeno.2003.12.007]