Alternative titles; symbolsLAG1, S. CEREVISIAE, HOMOLOG OF, 4; LASS4TRAM HOMOLOG 1; TRH1HGNC Approved Gene Symbol: CERS4Cytogenetic location: 19p13.2 Genomic...
Alternative titles; symbols
HGNC Approved Gene Symbol: CERS4
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:8,209,328-8,262,432 (from NCBI)
Ceramide, the structural backbone of sphingolipids, is also an important signaling molecule in apoptosis, differentiation, and the cell cycle. Ceramide synthases (EC 18.104.22.168), such as CERS4, are conserved from yeast to mammals and are essential for de novo ceramide synthesis, which involves the formation of an amide linkage between a fatty acyl-CoA and a sphingoid base (summary by Venkataraman and Futerman (2002) and Riebeling et al. (2003)).
▼ Cloning and Expression
By database analysis, Winter and Ponting (2002) identified over 70 proteins, including mouse Cers4, which they called Trh1, as members of a family of proteins related to TRAM (TRAM1; 605190), yeast Lag1 (see 606919), and CLN8 (607837). All of these proteins contain a conserved TRAM-Lag1-CLN8 (TLC) domain consisting of 5 transmembrane regions. TRH proteins, such as mouse Trh1, also have an additional transmembrane domain followed by a homeobox domain N-terminal to the TLC domain.
Using quantitative RT-PCR, Riebeling et al. (2003) detected ubiquitous expression of Trh1 in mouse tissues, with highest expression in skin and lowest expression in liver. Confocal microscopy demonstrated localization of mouse Trh1 to the endoplasmic reticulum in transfected cells.
Bertrand et al. (2021) analyzed the gene expression of the ceramide synthase genes TLCD3A (611627), TLCD3B (615175), and CERS1 (606919) 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 showing the highest expression in the adult retina, whereas CERS5 (615335) and CERS6 showed higher expression in fetal retina. CERS2 (606920) was highly and prevalently expressed in other tissues.
Gross (2013) mapped the CERS4 gene to chromosome 19p13.2 based on an alignment of the CERS4 sequence (GenBank AK222621) with the genomic sequence (GRCh37).
▼ Gene Function
Using metabolic labeling, Riebeling et al. (2003) found that overexpression of mouse Trh1 or Trh4 (CERS5; 615335) in human embryonic kidney cells resulted in an increase in tritiated glucosylceramide. Cells overexpressing Trh1 exhibited a strong increase in N-linked stearoyl (C18), arachidoyl (C20), and, to a lesser extent, behenoyl (C22) ceramides, mono- and dihexosyl ceramides, and sphingomyelin. In contrast, cells overexpressing Trh4 showed increased expression of N-linked palmitoyl (C16) sphingolipids, with no notable differences in other fatty acids. Riebeling et al. (2003) concluded that Lag1 family members, such as Trh1 and Trh4, regulate (dihydro)ceramide synthases responsible for the production of sphingolipids containing different fatty acids.
▼ Molecular Genetics
Using oligogenic and single quantitative trait locus linkage analysis, followed by exome sequence analysis, Rosenthal et al. (2011) provided evidence of an association between activity of phospholipid transfer protein (PLTP; 172425) and coding variation in the LASS4 gene in 1 family. They replicated the finding in 3 additional families.