Alternative titles; symbols
HGNC Approved Gene Symbol: CERS2
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38) : 1:150,965,186-150,974,835 (from NCBI)
Ceramides form the lipid backbone of all complex sphingolipids and are important signaling molecules. Ceramides are synthesized de novo by N-acylation of a sphingoid long chain base by a family of ceramide synthases (EC 2.3.1.24), each of which uses a restricted subset of acyl-CoAs for N-acylation. CERS2 uses very long acyl chain CoAs (i.e., C22-C24) (summary by Ben-David et al., 2011).
Longevity assurance gene-1 (Lag1) is preferentially expressed in young yeast, i.e., yeast cells that have undergone a small number of cell divisions. Yeast life span can be increased or decreased by mutation or overexpression of this gene. By EST database searching for homologs of Lag1, followed by 5-prime RACE, Pan et al. (2001) identified a cDNA encoding LASS2. The deduced 230-amino acid protein is 29% identical to LASS1 (CERS1; 606919) over 224 amino acids. It has 4 transmembrane helices (2 fewer than most Lag1 homologs), a Lag1 motif, and a C-terminal acidic domain. Northern blot analysis revealed expression of a 2.4-kb transcript in kidney and liver, with lower levels in brain, heart, placenta, and lung.
Using real-time quantitative PCR, Laviad et al. (2008) found that Cers2 was expressed in all mouse tissues examined, with highest levels in liver and kidney. Epitope-tagged human CERS2 localized to endoplasmic reticulum of transfected HEK293 cells.
By yeast 2-hybrid screening of liver and fetal brain cDNA libraries with LASS2 as bait, followed by GST pull-down assays, Pan et al. (2001) showed that LASS2 interacted with asialoglycoprotein receptor-1 (ASGR1; 108360) and -2 (ASGR2; 108361), the C-terminal half of OCT1 (SLC22A1; 602607), and ATP6L (108745). Expression of LASS2 in hepatocellular carcinoma cell lines led to suppression of cancer cell growth.
By assaying HEK293 cells overexpressing human CERS2, Laviad et al. (2008) found that CERS2 used a wide range of acyl-CoAs, synthesizing ceramides containing C20:0, C22:0, C24:1, C24:0, C26:1, and C26:0 fatty acids. CERS2 synthesized only insignificant amounts of C18:0 ceramide, and no C16:0 ceramide. Laviad et al. (2008) noted that the 2 mouse tissues with highest Cers2 mRNA, kidney and liver, also had the highest proportion of C22- and C24-ceramides. Sphingosine-1-phosphate (S1P) inhibited CERS2 activity in a noncompetitive manner via 2 motifs showing significant similarity to S1P receptors (see 601974). Simultaneous alanine substitution of arg230 and arg325 within these motifs completely abolished the inhibitory effect of S1P on CERS2 activity without affecting basal CERS2 activity.
Bertrand et al. (2021) analyzed the gene expression of the ceramide synthase genes TLCD3A (611627), TLCD3B (615175), and CERS1 to CERS6 (615336) in 18 different human tissues based on RNA-seq data. TLCD3B showed high expression in the adult retina, with higher expression in the macula than in the periphery. Differential expression of CERSs across different tissues was observed, with CERS4 (615334) showing the highest expression in the adult retina, whereas CERS5 (615335) and CERS6 showed higher expression in fetal retina. CERS2 was highly and prevalently expressed in other tissues.
Laviad et al. (2008) determined that the CERS2 gene spans almost 10 kb and that the surrounding regions contain CpG and Alu elements.
Pan et al. (2001) mapped the CERS2 gene to chromosome 1q11 by radiation hybrid analysis.
Pewzner-Jung et al. (2010) found that Cers2 -/- mice had reduced life span compared with wildtype mice. Cers2 -/- mice could survive for at least 20 months, but they had elevated C16-ceramide and sphinganine levels and developed a liver phenotype consistent with ongoing metabolic dysfunction. Cers2 -/- mice exhibited severe nonzonal hepatopathy from about 30 days of age, when Cers2 expression peaked in wildtype mice, and displayed increased rates of hepatocyte proliferation and apoptosis. Older Cers2 -/- mice showed pronounced hepatocellular anisocytosis, widespread formation of nodules of regenerative hepatocellular hyperplasia, progressive hepatomegaly, and noninvasive hepatocellular carcinoma. Expression analysis in Cers2 -/- liver revealed upregulation of genes associated with cell cycle, protein transport, cell-cell interactions, and apoptosis, and downregulation of genes associated with intermediary metabolism, including amino acid, lipid, and steroid metabolism and adipocyte signaling. Cers2 -/- mice showed no renal changes or pathology.
Ben-David et al. (2011) found that Cers2 -/- mice developed abnormal motor behavior, including generalized and symmetrical myoclonic jerks and sensitivity to auditory stimuli. Electroencephalogram recordings revealed abnormally fast rhythmic activity, suggesting general cortical dysfunction. Ben-David et al. (2011) showed that ceramide composition of wildtype mouse brain changed during development, with C22-C24-galactosylceramide (GalCer) and 2-hydroxy-C22-C24-GalCer dominating during active myelination between birth and 1 month of age. Cers2 -/- mice exhibited profound alterations in lipid composition compared with wildtype mice at 1 month of age, with elevated content of hydroxy-C18-GalCer and reduced levels of C22-C24-GalCer and 2-hydroxy-C22-C24-GalCer. Histologic examination of Cers2 -/- brain in the first months of life revealed progressive myelin degeneration and detachment, bilateral and symmetrical vacuolization of white and gray matter, localized gliosis, particularly in globus pallidus, and generalized astrogliosis and microglial activation. Vacuoles appeared to be due to ballooning of myelin sheath. Storage material was also detected in astrocyte lysosomes. Ben-David et al. (2011) concluded that CERS2 is required for maintenance, but not formation, of the myelin sheath.
Ben-David, O., Pewzner-Jung, Y., Brenner, O., Laviad, E. L., Kogot-Levin, A., Weissberg, I., Biton, I. E., Pienik, R., Wang, E., Kelly, S., Alroy, J., Raas-Rothschild, A., Friedman, A., Brugger, B., Merrill, A. H., Jr., Futerman, A. H. Encephalopathy caused by ablation of very long acyl chain ceramide synthesis may be largely due to reduced galactosylceramide levels. J. Biol. Chem. 286: 30022-30033, 2011. [PubMed: 21705317] [Full Text: https://doi.org/10.1074/jbc.M111.261206]
Bertrand, R. E., Wang, J., Xiong, K. H., Thangavel, C., Qian, X., Ba-Abbad, R., Liang, Q., Simoes, R. T., Sampaio, S. A. M., Carss, K. J., Raymond, F. L., Robson, A. G., Webster, A. R., Arno, G., Porto, F. B. O., Chen, R. Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy. Genet. Med. 23: 488-497, 2021. [PubMed: 33077892] [Full Text: https://doi.org/10.1038/s41436-020-01003-x]
Laviad, E. L., Albee, L., Pankova-Kholmyansky, I., Epstein, S., Park, H., Merrill, A. H., Jr., Futerman, A. H. Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J. Biol. Chem. 283: 5677-5684, 2008. [PubMed: 18165233] [Full Text: https://doi.org/10.1074/jbc.M707386200]
Pan, H., Qin, W.-X., Huo, K.-K., Wan, D.-F., Yu, Y., Xu, Z.-G., Hu, Q.-D., Gu, K. T., Zhou, X.-M., Jiang, H.-Q., Zhang, P.-P., Huang, Y., Li, Y.-Y., Gu, J.-R. Cloning, mapping, and characterization of a human homologue of the yeast longevity assurance gene LAG1. Genomics 77: 58-64, 2001. [PubMed: 11543633] [Full Text: https://doi.org/10.1006/geno.2001.6614]
Pewzner-Jung, Y., Brenner, O., Braun, S., Laviad, E. L., Ben-Dor, S., Feldmesser, E., Horn-Saban, S., Amann-Zalcenstein, D., Raanan, C., Berkutzki, T., Erez-Roman, R., Ben-David, O., Levy, M., Holzman, D., Park, H., Nyska, A., Merrill, A. H., Jr., Futerman, A. H. A critical role for ceramide synthase 2 in liver homeostasis: II. Insights into molecular changes leading to hepatopathy. J. Biol. Chem. 285: 10911-10923, 2010. [PubMed: 20110366] [Full Text: https://doi.org/10.1074/jbc.M109.077610]