Disease:


  • OMIM ID: 609280 . 609280
  • OMIM diseaseName:
  • OMIM diseaseClinical_Synopsis:
  • OMIM diseaseText: DESCRIPTION EIF2AK4 belongs to a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2S1; 603907) to downregulate protein synthesis in response to varied cellular stresses (Berlanga et al., 1999). CLONING Berlanga et al. (1999) cloned mouse Eif2ak4, which they designated Gcn2. The deduced 1,648-amino acid protein has a calculated molecular mass of 186.4 kD. Gcn2 contains all 12 conserved catalytic subdomains of eukaryotic serine/threonine protein kinases. The N-terminal half of Gcn2 contains a degenerate kinase domain, followed by a central catalytic domain with a large insert typical of EIF2-alpha kinases. The C-terminal half of Gcn2 contains 3 motifs conserved among class II aminoacyl-tRNA synthetases (see 138295). Northern blot analysis detected Gcn2 expression in all mouse tissues examined, with highest levels in liver and brain. Western blot analysis detected Gcn2 in mouse liver extracts at an apparent molecular mass of about 190 kD. By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned EIF2AK4, which they designated KIAA1338. The 3-prime UTR of the transcript contains an Alu element. The deduced 1,495-amino acid protein shares significant similarity with S. cerevisiae Gcn2. RT-PCR ELISA detected moderate to high EIF2AK4 expression in all tissues and specific brain regions examined. Highest expression was detected in adult liver, ovary, and amygdala. Fetal liver showed lower EIF2AK4 expression than adult liver. GENE FUNCTION Berlanga et al. (1999) demonstrated that Gcn2 immunopurified from mouse liver extracts could phosphorylate rabbit Eif2 in vitro. Serum starvation increased the level of phosphorylated EIF2-alpha more than 2-fold in human embryonic kidney cells transfected with mouse Eif2ak4. Costa-Mattioli et al. (2005) reported a unique feature of hippocampal slices from Gcn2-null mice: in CA1, a single 100-Hz train induced a strong and sustained long-term potentiation (late LTP or L-LTP), which was dependent on transcription and translation. In contrast, stimulation that elicited L-LTP in wildtype slices, such as four 100-Hz trains or forskolin, failed to evoke L-LTP in Gcn2-null slices. This aberrant synaptic plasticity was mirrored in the behavior of Gcn2-null mice in the Morris water maze: after weak training, their spatial memory was enhanced, but it was impaired after more intense training. Activated GCN2 stimulates mRNA translation of ATF4 (604064), an antagonist of cAMP response element-binding protein (CREB; (123810)). Thus, in the hippocampus of Gcn2-null mice, the expression of ATF4 was reduced and CREB activity was increased. Costa-Mattioli et al. (2005) concluded that their study provided genetic, physiologic, behavioral, and molecular evidence that GCN2 regulates synaptic plasticity, as well as learning and memory, through modulation of the ATF4/CREB pathway. MAPPING Hartz (2005) mapped the EIF2AK4 gene to chromosome 15q15.1 based on an alignment of the EIF2AK4 sequence (GenBank GENBANK AB037759) with the genomic sequence. ANIMAL MODEL Zhang et al. (2002) found that Gcn2 -/- mice were viable and fertile and exhibited no phenotypic abnormalities under standard growth conditions. However, prenatal and neonatal mortality were significantly increased in Gcn2 -/- mice whose mothers were reared on leucine-, tryptophan-, or glycine-deficient diets during gestation. Leucine deprivation produced the most pronounced effect. Cultured embryonic stem cells derived from Gcn2 -/- mice failed to show the normal induction of Eif2-alpha phosphorylation following leucine deprivation. Liver perfusion experiments in wildtype mice showed that histidine limitation in the presence of the histamine precursor histidinol induced a 2-fold increase in Eif2-alpha phosphorylation and a concomitant reduction in Eif2b (see 606686). These responses were ablated in Gcn2 -/- livers. Guo and Cavener (2007) found that lipid synthesis was repressed in the livers of wildtype mice during prolonged leucine deprivation, whereas lipid synthesis continued unabated in Gcn2 -/- mice, resulting in severe liver steatosis. Failure to downregulate lipid synthesis resulted from persistent expression of Srebp1c (SREBF1; 184756) and its downstream transcriptional targets underlying fatty acid and triglyceride synthesis.
  • OMIM diseaseSee_Also:
  • OMIM diseaseAllelic_Variants:
  • OMIM diseaseCreation_Date: Patricia A. Hartz: 3/28/2005
  • OMIM diseaseEdit_History_Data: wwang: 04/25/2007 alopez: 10/12/2005 terry: 10/10/2005 mgross: 3/28/2005
  • OMIM diseaseContributors: Patricia A. Hartz - updated: 04/25/2007 Ada Hamosh - updated: 10/10/2005
  • OMIM diseaseReference: 1. Berlanga, J. J.; Santoyo, J.; de Haro, C.: Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2-alpha kinase. Europ. J. Biochem. 265: 754-762, 1999. 2. Costa-Mattioli, M.; Gobert, D.; Harding, H.; Herdy, B.; Azzi, M.; Bruno, M.; Bidinosti, M.; Ben Mamou, C.; Marcinkiewicz, E.; Yoshida, M.; Imataka, H.; Cuello, A. C.; Seidah, N.; Sossin, W.; Lacaille, J.-C.; Ron, D.; Nader, K.; Sonenberg, N.: Translational control of hippocampal synaptic plasticity and memory by the elF2-alpha kinase GCN2. Nature 436: 1166-1170, 2005. 3. Guo, F.; Cavener, D. R.: The GCN2 eIF2-alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab. 5: 103-114, 2007. 4. Hartz, P. A.: Personal Communication. Baltimore, Md. 3/28/2005. 5. Nagase, T.; Kikuno, R.; Ishikawa, K.; Hirosawa, M.; Ohara, O.: Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. 6. Zhang, P.; McGrath, B. C.; Reinert, J.; Olsen, D. S.; Lei, L.; Gill, S.; Wek, S. A.; Vattem, K. M.; Wek, R. C.; Kimball, S. R.; Jefferson, L. S.; Cavener, D. R.: The GCN2 eIF2-alpha kinase is required for adaptation to amino acid deprivation in mice. Molec. Cell. Biol. 22: 6681-6688, 2002.