Alternative titles; symbols
HGNC Approved Gene Symbol: BTN1A1
Cytogenetic location: 6p22.2 Genomic coordinates (GRCh38): 6:26,500,303-26,510,425 (from NCBI)
The butyrophilin (BTN) genes are a group of major histocompatibility complex (MHC)-associated genes that encode type I membrane proteins with 2 extracellular immunoglobulin (Ig) domains and an intracellular B30.2 (PRYSPRY) domain. Three subfamilies of human BTN genes are located in the MHC class I region: the single-copy BTN1A1 gene and the BTN2 (e.g., BTN2A1; 613590) and BTN3 (e.g., BNT3A1; 613593) genes, which have undergone tandem duplication, resulting in 3 copies of each. BNT1A1 is required for secretion of milk lipid droplets during lactation, and this function has been attributed to its B30.2 domain (summary by Smith et al., 2010).
Ogg et al. (1996) cloned mouse Btn. Btn mRNA was detected specifically in mouse mammary gland by RNase protection analysis. Expression increased during the last half of pregnancy and was maximal during lactation.
Using quantitative RT-PCR of mouse tissues, Smith et al. (2010) detected high Btn1a1 mRNA in lactating mammary tissue, with much lower expression in virgin mammary tissue, spleen, thymus, and several other tissues examined. Western blot analysis revealed Btn1a1 in lactating mouse mammary tissue only. Immunohistochemical analysis of mouse thymus showed expression of Btn1a1 in thymic stroma and on thymic epithelial cells.
Mather and Jack (1993) reviewed the molecular and cellular biology of bovine butyrophilin, the major protein of milk fat globule membrane.
Robenek et al. (2006) found that BTN in the residual plasma membrane of the fat globule envelope was concentrated in a network of ridges that were tightly apposed to the monolayer derived from the secretory granule. The ridges coincided with BTN labeling in the globule monolayer. Robenek et al. (2006) proposed that milk fat globule secretion is controlled by interaction between plasma membrane BTN and BTN in the secretory granule phospholipid monolayer rather than by binding of BTN-xanthine oxidoreductase (XDH; 607633) complexes to secretory granule adipophilin (ADRP; 103195).
Smith et al. (2010) found that mouse Btn1a1 and Btn2a2 (613591) bound activated T cells, inhibited proliferation of Cd4 (186940)- and Cd8 (see 186910)-positive lymphocytes, inhibited T-cell metabolism, and blocked cytokine production. They concluded that BTNs have a coinhibitory role in T-cell activation.
Rhodes et al. (2001) determined that the BTN1A1 gene spans approximately 12 kb and contains 7 coding exons.
Vernet et al. (1993) found that the human butyrophilin gene is localized in the major histocompatibility complex (MHC) class I region of 6p and suggested that it may have arisen relatively recently in evolution by the shuffling of exons between 2 ancestral gene families. In the mouse, the butyrophilin gene is associated with a syntenic group of MHC-related genes on chromosome 13 and is not associated with the MHC on chromosome 17 (Amadou et al., 1995). Ashwell et al. (1996) showed that the bovine butyrophilin gene is located on chromosome 23. Bovine chromosome 23 exhibits high homology with human chromosome 6 (Solinas-Toldo et al., 1995).
Tazi-Ahnini et al. (1997) identified additional members of the butyrophilin gene family in the telomeric region of the major histocompatibility complex.
By genomic sequence analysis, Rhodes et al. (2001) mapped the human BTN gene cluster to chromosome 6p22.1, about 4 Mb telomeric to the classical MHC class I genes. BTN1A1 is the most centromeric BTN gene and is located about 25 kb from the closest BTN gene, BTN2A1 (613590).
To determine the function of BTN1A1 in milk secretion, Ogg et al. (2004) ablated the gene in mice and analyzed the lactation phenotype of homozygous null animals. Two mutant mouse lines were generated in which expression of the gene was either disrupted or eliminated. The regulated secretion of milk lipid droplets was severely compromised in both mutant mouse lines in comparison to wildtype animals. Large pools of triacylglycerol accumulated in the cytoplasm of secretory cells, and lipid droplets escaped from the apical surface with disrupted outer membranes. In contrast, there was no significant difference between wildtype and null animals and the relative amounts of skim milk proteins secreted from Golgi-derived secretory vesicles. Approximately half the pups suckling null animals died within the first 20 days, and weaning weights for the surviving pups were 60 to 80% of those suckling wildtype mice. Ogg et al. (2004) concluded that expression of BTN1A1 is essential for the regulated secretion of milk lipid droplets. They speculated that the gene functions either as a structural protein or as a signaling receptor by binding to XDH.
Amadou, C., Ribouchon, M. T., Mattei, M. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Avoustin, P., Pontarotti, P. Localization of new genes and markers to the distal part of the human major histocompatibility complex (MHC) region and comparison with the mouse: new insights into the evolution of mammalian genomes. Genomics 26: 9-20, 1995. [PubMed: 7782091] [Full Text: https://doi.org/10.1016/0888-7543(95)80077-y]
Ashwell, M. S., Ogg, S. L., Mather, I. H. The bovine butyrophilin gene maps to chromosome 23. Anim. Genet. 27: 171-173, 1996. [PubMed: 8759115] [Full Text: https://doi.org/10.1111/j.1365-2052.1996.tb00945.x]
Mather, I. H., Jack, L. J. W. A review of molecular and cellular biology of butyrophilin, the major protein of bovine milk fat globule membrane. J. Dairy Sci. 76: 3832-3850, 1993. [PubMed: 8132890] [Full Text: https://doi.org/10.3168/jds.s0022-0302(93)77726-7]
Ogg, S. L., Komaragiri, M. V. S., Mather, I. H. Structural organization and mammary-specific expression of the butyrophilin gene. Mammalian Genome 7: 900-905, 1996. [PubMed: 8995761] [Full Text: https://doi.org/10.1007/s003359900265]
Ogg, S. L., Weldon, A. K., Dobbie, L., Smith, A. J. H., Mather, I. H. Expression of butyrophilin (Btn1a1) in lactating mammary gland is essential for the regulated secretion of milk-lipid droplets. Proc. Nat. Acad. Sci. 101: 10084-10089, 2004. [PubMed: 15226505] [Full Text: https://doi.org/10.1073/pnas.0402930101]
Rhodes, D. A., Stammers, M., Malcherek, G., Beck, S., Trowsdale, J. The cluster of BTN genes in the extended major histocompatibility complex. Genomics 71: 351-362, 2001. [PubMed: 11170752] [Full Text: https://doi.org/10.1006/geno.2000.6406]
Robenek, H., Hofnagel, O., Buers, I., Lorkowski, S., Schnoor, M., Robenek, M. J., Heid, H., Troyer, D., Severs, N. J. Butyrophilin controls milk fat globule secretion. Proc. Nat. Acad. Sci. 103: 10385-10390, 2006. [PubMed: 16801554] [Full Text: https://doi.org/10.1073/pnas.0600795103]
Smith, I. A., Knezevic, B. R., Ammann, J. U., Rhodes, D. A., Aw, D., Palmer, D. B., Mather, I. H., Trowsdale, J. BTN1A1, the mammary gland butyrophilin, and BTN2A2 are both inhibitors of T cell activation. J. Immun. 184: 3514-3525, 2010. [PubMed: 20208008] [Full Text: https://doi.org/10.4049/jimmunol.0900416]
Solinas-Toldo, S., Lengauer, C., Fries, R. Comparative genome map of human and cattle. Genomics 27: 489-496, 1995. [PubMed: 7558031] [Full Text: https://doi.org/10.1006/geno.1995.1081]
Tazi-Ahnini, R., Henry, J., Offer, C., Bouissou-Bouchouata, C., Mather, I. H., Pontarotti, P. Cloning, localization, and structure of new members of the butyrophilin gene family in the juxta-telomeric region of the major histocompatibility complex. Immunogenetics 47: 55-63, 1997. [PubMed: 9382921] [Full Text: https://doi.org/10.1007/s002510050326]
Vernet, C., Boretto, J., Mattei, M.-G., Takahashi, M., Jack, L. J. W., Mather, I. H., Rouquier, S., Pontarotti, P. Evolutionary study of multigenic families mapping close to the human MHC class I region. J. Molec. Evol. 37: 600-612, 1993. [PubMed: 8114113] [Full Text: https://doi.org/10.1007/BF00182746]