Alternative titles; symbols
HGNC Approved Gene Symbol: CSN2
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:69,955,256-69,965,728 (from NCBI)
Caseins are the major components of human milk and are the primary source of amino acids, calcium, and phosphate for the suckling infant. The human caseins include alpha-S1- (115450) and beta-casein, which are the substrates for protein kinase and precipitate in the presence of calcium (so-called calcium-sensitive caseins), and kappa-casein (601695), which prevents the precipitation of the other caseins by calcium through micelle formation (summary by Fujiwara et al., 1997).
Beta-casein is the major casein in human milk, accounting for as much as 30% of its total protein mass. In addition to being the primary source of essential amino acids, beta-casein, in concert with kappa-casein, forms micelles that transport calcium and phosphorus to the developing infant.
Menon and Ham (1989) and Lonnerdal et al. (1990) cloned cDNAs for human beta-casein. The deduced protein consists of 210 amino acids with a signal peptide of 15 amino acids.
Comparison with other species indicates that the caseins are among the most rapidly evolving proteins (Dayhoff, 1976). Nevertheless, a number of well-conserved residues are distributed along its entire length. These residues are thought to play an important role in conserving the 3-dimensional structure of the protein.
Lonnerdal et al. (1990) determined that the sequence of human beta-casein shows 45 to 62% homology to those of bovine, ovine, rat, and mouse beta-caseins.
Menon et al. (1992) showed that in relation to the beta-casein of other species, the mature protein in the human shows a deletion of amino acids encoded by exon 3. They concluded that an interruption of the polypyrimidine tract adjacent to the 5-prime end of the exon 3 sequence may account for the omission of the exon from human beta-casein mRNA. They stated that a broader sampling would be required for a firm conclusion that exon 3 is never expressed in human beta-casein. Nevertheless, the lack of expression of exon 3 is at the very least a frequent occurrence in humans and may well be species-specific. Exon 3 encodes 9 residues, including 2 additional phosphorylation sites, serine residues 7 and 8. The N-terminal phosphoserine/phosphothreonine amino acids of beta-casein are crucial to the biologic function of the molecule, and variations in their number could affect the overall quality of milk.
Using PCR on genomic DNA from somatic cell hybrids, Menon et al. (1992) localized the CSN2 gene to chromosome 4pter-q21. All members of the casein multigene family are located in a 200-kb region on bovine chromosome 6. Mouse caseins alpha, beta, and gamma have been localized to chromosome 5.
McConkey et al. (1996) used fluorescence in situ hybridization (FISH) and beta-casein phage clones to assign the human CSN2 gene to 4q13-q21. They reported that CSN2 maps to 3p13-p12 in chimpanzees; chimpanzee chromosome 3 is homologous to human chromosome 4. This finding confirmed the presence of the pericentric inversion that distinguishes the 2 species.
Fujiwara et al. (1997) demonstrated that in the human the alpha-S1 beta, and kappa forms of casein are closely linked and arranged in that order, with about 10 kb between the first 2 and about 300 kb between the latter 2. By FISH, they mapped the casein gene family to 4q21.1.
Rijnkels et al. (1997) concluded that the human casein 'locus' comprises at least 4 casein genes: 3 genes encoding calcium-sensitive, casein-like genes and 1 kappa-like casein gene.
Chen et al. (1995) reported linkage of the casein genes within 700 kb of the albumin (103600) gene cluster, suggesting that the casein genes are located on 4q13.
In cattle, 4 casein genes, alpha-S1, alpha-S2, beta- and kappa are closely physically linked within a region of 200 to 300 kb (Ferretti et al., 1990; Threadgill and Womack, 1990).
CSN2 gene transcription is controlled primarily by a composite response element (CoRE) that integrates signaling from the lactogenic hormones, prolactin (PRL; 176760), insulin (176730), and hydrocortisone in mammary epithelial cells. This CoRE contains binding sites for STAT5 (601511) and C/EBP-beta (189965) and several half-sites for glucocorticoid receptor (GR; 138040). To examine how interactions among these 3 transcription factors regulate CSN2 gene transcription, Wyszomierski and Rosen (2001) employed a COS cell reconstitution system. Cooperative transactivation was observed when all 3 factors were expressed, but unexpectedly was not seen between STAT5 and C/EBP-beta in the absence of full-length, transcriptionally active GR. Cooperativity required the amino-terminal transactivation domain of C/EBP-beta, and neither C/EBP-alpha (116897) nor C/EBP-delta (116898) was able to substitute for C/EBP-beta when cotransfected with STAT5 and GR. Different GR determinants were needed for transcriptional cooperation between STAT5 and GR as compared with those required for all 3 transcription factors.
Chen, C.-S., Bejeck, B. E., Kersey, J. H. A mapping study of 13 genes on human chromosome bands 4q11-q25. Cytogenet. Cell Genet. 69: 260-265, 1995. [PubMed: 7698025] [Full Text: https://doi.org/10.1159/000133976]
Dayhoff, M. O. Atlas of Protein Sequence and Structure. Silver Spring, Md.: National Biomedical Research Foundation (pub.) 1976.
Ferretti, L., Leone, P., Sgaramella, V. Long range restriction analysis of the bovine casein genes. Nucleic Acids Res. 18: 6829-6833, 1990. [PubMed: 2263448] [Full Text: https://doi.org/10.1093/nar/18.23.6829]
Fujiwara, Y., Miwa, M., Nogami, M., Okumura, K., Nobori, T., Suzuki, T., Ueda, M. Genomic organization and chromosomal localization of the human casein gene family. Hum. Genet. 99: 368-373, 1997. [PubMed: 9050925] [Full Text: https://doi.org/10.1007/s004390050374]
Lonnerdal, B., Bergstrom, S., Andersson, Y., Hjalmarsson, K., Sundqvist, A. K., Hernell, O. Cloning and sequencing of a cDNA encoding human milk beta-casein. FEBS Lett. 269: 153-156, 1990. [PubMed: 2387396] [Full Text: https://doi.org/10.1016/0014-5793(90)81142-b]
McConkey, E. H., Menon, R., Williams, G., Baker, E., Sutherland, G. R. Assignment of the gene for beta-casein (CSN2) to 4q13-q21 in humans and 3p13-p12 in chimpanzees. Cytogenet. Cell Genet. 72: 60-62, 1996. [PubMed: 8565637] [Full Text: https://doi.org/10.1159/000134163]
Menon, R. S., Chang, Y.-F., Jeffers, K. F., Ham, R. G. Exon skipping in human beta-casein. Genomics 12: 13-17, 1992. [PubMed: 1370811] [Full Text: https://doi.org/10.1016/0888-7543(92)90400-m]
Menon, R. S., Chang, Y.-F., Jeffers, K. F., Jones, C., Ham, R. G. Regional localization of human beta-casein gene (CSN2) to 4pter-q21. Genomics 13: 225-226, 1992. [PubMed: 1577486] [Full Text: https://doi.org/10.1016/0888-7543(92)90227-j]
Menon, R. S., Ham, R. G. Human beta-casein: partial cDNA sequence and apparent polymorphism. Nucleic Acids Res. 17: 2869, 1989. [PubMed: 2717418] [Full Text: https://doi.org/10.1093/nar/17.7.2869]
Rijnkels, M., Meershoek, E., de Boer, H. A., Pieper, F. R. Physical map and localization of the human casein gene locus. Mammalian Genome 8: 285-286, 1997. [PubMed: 9096114] [Full Text: https://doi.org/10.1007/s003359900413]
Threadgill, D. W., Womack, J. E. Genomic analysis of the major bovine milk protein genes. Nucleic Acids Res. 18: 6935-6942, 1990. [PubMed: 1979856] [Full Text: https://doi.org/10.1093/nar/18.23.6935]
Wyszomierski, S. L., Rosen, J. M. Cooperative effects of STAT5 (signal transducer and activator of transcription 5) and C/EBP beta (CCAAT/enhancer-binding protein-beta) on beta-casein gene transcription are mediated by the glucocorticoid receptor. Molec. Endocr. 15: 228-240, 2001. [PubMed: 11158330] [Full Text: https://doi.org/10.1210/mend.15.2.0597]