Alternative titles; symbols
HGNC Approved Gene Symbol: CAMK4
Cytogenetic location: 5q22.1 Genomic coordinates (GRCh38) : 5:111,223,583-111,494,886 (from NCBI)
The CAMK4 gene encodes an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by Zech et al., 2018).
Protein phosphorylation, a prominent activity in the brain, apparently plays an important role in several neural functions such as neural transmitter release, ion channel modulation, and axoplasmic transport. Sikela et al. (1989) identified cDNA clones corresponding to a brain Ca(2+)/calmodulin-dependent protein kinase, which they referred to as brain CaM kinase IV (CAMK4). On the basis of Western blot analysis, this kinase appeared to be restricted to brain in the rat; interestingly, it was not detected in the brain of the newborn, but became detectable within a few days after birth.
By immunostaining of adult mouse brain sections, Wei et al. (2002) found Camk4-labeled neurons in the hippocampus, amygdala, anterior cingulate cortex, somatosensory cortex, and insular cortex.
By Southern blot analysis, Sikela et al. (1989) showed that the CAMK4 gene is present in single copy in the mouse and human genomes. Analysis of DNA from hybrid cells showed that the gene is located on human chromosome 5, and in situ hybridization indicated that the location is 5q21-q23. By Southern blot analysis of Chinese hamster/mouse somatic cell hybrids, Sikela et al. (1990) demonstrated that the homologous mouse locus, Camk4, maps to chromosome 18. Analysis of interspecific backcrosses positioned Camk4 in the centromeric region near 2 mutations known to affect neurologic function and fertility. Sikela et al. (1990) raised the possibility that a defect in Camk4 may be responsible for 1 of these mutant phenotypes.
Koga et al. (2012) found that knockdown of CAMK4 via small interfering RNA in T cells from patients with systemic lupus erythematosus (SLE; 152700) resulted in augmentation of the percentage of CD25 (IL2RA; 147730)-positive/FOXP3 (300292)-positive regulatory T cells. They concluded that CAMK4 is important in the generation and function of regulatory T cells in patients with SLE.
Associations Pending Confirmation
For discussion of a possible association between a neurodevelopmental disorder with hyperkinetic movements and variation in the CAMK4 gene, see 114080.0001.
Camk4 is a multifunctional serine/threonine protein kinase with limited tissue distribution that has been implicated in transcriptional regulation in lymphocytes, neurons, and male germ cells. In the mouse testis, however, Camk4 is expressed in spermatids and associated with chromatin and nuclear matrix. Elongating spermatids are not transcriptionally active, raising the possibility that Camk4 has a novel function in male germ cells. To investigate the role of Camk4 in spermatogenesis, Wu et al. (2000) generated mice with a targeted deletion of the Camk4 gene. Male Camk4 -/- mice were infertile with impairment of spermiogenesis in late elongating spermatids. The sequential deposition of sperm basic nuclear proteins on chromatin was disrupted, with a specific loss of protamine-2 (182890) and prolonged retention of transition protein-2 (190232) in step-15 spermatids. Protamine-2 is phosphorylated by Camk4 in vitro, implicating a connection between Camk4 signaling and the exchange of basic nuclear proteins in mammalian male germ cells. Defects in protamine-2 have been identified in sperm of infertile men, suggesting that the results of Wu et al. (2000) may have clinical implications for the understanding of human male infertility.
CAMK4 is implicated in the regulation of CRE-dependent transcription. To investigate the role of this kinase in neuronal plasticity and memory, Kang et al. (2001) generated transgenic mice in which the expression of a dominant-negative form of Camk4 was restricted to the postnatal forebrain. In these transgenic mice, activity-induced Creb (123810) phosphorylation and Fos (164810) expression were significantly attenuated. Hippocampal late long-term potentiation (LTP) was also impaired, whereas basic synaptic function and early LTP were unaffected. These deficits correlated with impairments in long-term memory, specifically in its consolidation/retention phase but not in the acquisition phase. The results indicated that neural activity-dependent CAMK4 signaling in the neuronal nucleus plays an important role in the consolidation/retention of hippocampus-dependent long-term memory.
Wei et al. (2002) studied pain and fear memory in Camk4-null mice. Behavioral responses to an acute noxious stimulus or to prolonged injury were identical in wildtype and Camk4-null mice, but fear memory was significantly reduced in the absence of Camk4. Brain sections of wildtype mice following fear conditioning showed phospho-Creb immunoreactivity, indicating Creb activation, in memory-related areas including the hippocampal CA1 region, basolateral amygdala, anterior cingulate cortex, primary somatosensory cortex, and agranular insular cortex. Brain sections of Camk4 -/- mice showed no evidence of fear-induced phospho-Creb in the somatosensory cortex and insular cortex and lower levels of phospho-Creb in the anterior cingulate cortex. Electrophysiologic studies indicated that Camk4 contributes to synaptic potentiation. Stimulation of brain slices induced significant synaptic potentiation in the anterior cingulate cortex, insular cortex, and somatosensory cortex of wildtype mice, but reduced or blocked potentiation in Camk4 -/- mice. Camk4 was also found to be required for calmodulin (see 114180) translocation in response to KCl application in the hippocampus, amygdala, anterior cingulate cortex, somatosensory cortex, and insular cortex. Wei et al. (2002) concluded that Camk4 is crucial in the trapping of Ca(2+)/calmodulin complexes in neuronal nuclei and in Creb phosphorylation and activation.
CAMK4 expression is developmentally regulated in T lymphocytes and is highest in CD4 (186940)-positive/CD8 (see 186910)-positive thymocytes. Using flow cytometric analysis, Raman et al. (2001) showed that thymocytes from mice lacking Camk4 had impaired thymocyte maturation, particularly in positive selection, and defective calcium-dependent gene transcription.
Wu et al. (2002) generated transgenic mice that selectively express in skeletal muscle a constitutively active form of calcium/calmodulin-dependent protein kinase-4. Skeletal muscles from these mice showed augmented mDNA replication and mitochondrial biogenesis, upregulation of mitochondrial enzymes involved in fatty acid metabolism and electron transport, and reduced susceptibility to fatigue during repetitive contractions. CAMK induced expression of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1; 604517), a master regulator of mitochondrial biogenesis in vivo, and activated the PGC1 gene promoter in cultured myocytes. Thus, Wu et al. (2002) concluded that a calcium-regulated signaling pathway controls mitochondrial biogenesis in mammalian cells.
MRL/lpr mice have decreased Il2 (147680) production and develop an SLE-like disease. By RT-PCR analysis, Koga et al. (2012) showed that T cells from MRL/lpr mice had increased nuclear Camk4. MRL/lpr mice lacking Camk4 had significantly prolonged survival, restoration of Cd4 T-cell Il2 production, and increased numbers of Cd4-positive/Cd25-positive/Foxp3-positive regulatory T cells. Koga et al. (2012) concluded that Camk4 is important in the generation and function of regulatory T cells in lupus-prone mice.
This variant is classified as a variant of unknown significance because its contribution to a neurodevelopmental disorder with hyperkinetic movements has not been confirmed.
In 28-year-old man, born of unrelated parents, with a neurodevelopmental disorder with hyperkinetic movements, Zech et al. (2018) identified a de novo heterozygous G-to-A transition in intron 10 of the CAMK4 gene (c.981+1G-A, NM_001744.4), resulting in a frameshift and premature termination (Lys303SerfsTer28) in the last exon of the gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 142), 1000 Genomes Project, or gnomAD databases, or in an in-house database of 12,000 control exomes. Analysis of patient cells showed that the mutation was not subject to nonsense-mediated mRNA decay; the expressed protein retained the protein kinase domain but lacked the autoregulatory domain. Analysis of patient cells showed increased phosphorylation of the CREB protein (123810), which is a downstream target of CAMK4, compared to controls. Treatment with an inhibitor of the upstream signaling molecule CAMKK (see, e.g., CAMKK1, 611411) reversed the overactivity of CAMK4. The findings were consistent with the mutation causing a gain of function in CAMK4 with increased constitutive signaling, which could potentially result in altered neuronal circuits. The patient presented at 3 years of age with global developmental delay, impaired intellectual development, and speech delay. He walked at 3 years, but had difficulty with gross and fine motor movements. The patient had moderate impaired intellectual development, autistic features, and behavioral abnormalities, but was able to attend special schools. He also had a mixed hyperkinetic movement disorder, including dystonia, myoclonus, and choreoathetosis that grew progressively worse during adolescence and was unresponsive to treatment. He did not have seizures. Brain imaging showed cerebellar atrophy.
Kang, H., Sun, L. D., Atkins, C. M., Soderling, T. R., Wilson, M. A., Tonegawa, S. An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106: 771-783, 2001. [PubMed: 11572782] [Full Text: https://doi.org/10.1016/s0092-8674(01)00497-4]
Koga, T., Ichinose, K., Mizui, M., Crispin, J. C., Tsokos, G. C. Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. J. Immun. 189: 3490-3496, 2012. [PubMed: 22942433] [Full Text: https://doi.org/10.4049/jimmunol.1201785]
Raman, V., Blaeser, F., Ho, N., Engle, D. L., Williams, C. B., Chatila, T. A. Requirement for Ca(2+)/calmodulin-dependent kinase type IV/Gr in setting the thymocyte selection threshold. J. Immun. 167: 6270-6278, 2001. [PubMed: 11714790] [Full Text: https://doi.org/10.4049/jimmunol.167.11.6270]
Sikela, J. M., Adamson, M. C., Wilson-Shaw, D., Kozak, C. A. Genetic mapping of the gene for Ca(2+)/calmodulin-dependent protein kinase IV (Camk-4) to mouse chromosome 18. Genomics 8: 579-582, 1990. [PubMed: 1981056] [Full Text: https://doi.org/10.1016/0888-7543(90)90048-y]
Sikela, J. M., Law, M. L., Kao, F.-T., Hartz, J. A., Wei, Q., Hahn, W. E. Chromosomal localization of the human gene for brain Ca(2+)/calmodulin-dependent protein kinase type IV. Genomics 4: 21-27, 1989. [PubMed: 2536634] [Full Text: https://doi.org/10.1016/0888-7543(89)90309-1]
Wei, F., Qiu, C.-S., Liauw, J., Robinson, D. A., Ho, N., Chatila, T., Zhuo, M. Calcium-calmodulin-dependent protein kinase IV is required for fear memory. Nature Neurosci. 5: 573-579, 2002. [PubMed: 12006982] [Full Text: https://doi.org/10.1038/nn0602-855]
Wu, H., Kanatous, S. B., Thurmond, F. A., Gallardo, T., Isotani, E., Bassel-Duby, R., Williams, R. S. Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296: 349-352, 2002. [PubMed: 11951046] [Full Text: https://doi.org/10.1126/science.1071163]
Wu, J. Y., Ribar, T. J., Cummings, D. E., Burton, K. A., McKnight, G. S., Means, A. R. Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4. Nature Genet. 25: 448-452, 2000. [PubMed: 10932193] [Full Text: https://doi.org/10.1038/78153]
Zech, M., Lam, D. D., Weber, S., Berutti, R., Polakova, K., Havrankova, P., Fecikova, A., Strom, T. M., Ruzicka, E., Jech, R., Winkelmann, J. A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder. Cold Spring Harbor Molec. Case Stud. 4: a003293, 2018. Note: Electronic Article. [PubMed: 30262571] [Full Text: https://doi.org/10.1101/mcs.a003293]