Alternative titles; symbols
HGNC Approved Gene Symbol: KLRA1P
Cytogenetic location: 12p13.2 Genomic coordinates (GRCh38) : 12:10,588,478-10,599,835 (from NCBI)
KLRA1P is related to the mouse Ly49 genes, but KLRA1P does not appear to encode a functional protein (Barten and Trowsdale, 1999).
Rodents have a family of over 9 lectin genes related to the Ly49 locus. Westgaard et al. (1998) identified an Ly49-related sequence in the human and designated the gene LY49L, also called KLRA1. Barten and Trowsdale (1999) showed that the genomic organization of the human LY49L gene is similar to that of the mouse homolog; however, exon 5 continues over a splice junction into the downstream intron and runs into a premature stop codon. They partially sequenced 2 alleles. Variation in the 2 sequences was confirmed in genomic and cDNA from different individuals, indicating a low level of polymorphism. Although genomic Southern blot analysis suggested the presence of additional Ly49-related sequences in the human genome, these were not within 130 kb of the LY49L locus. Barten and Trowsdale (1999) considered it unlikely that the LY49L gene encodes a functional protein. It could not be ruled out, however, that the truncated protein fulfills a specialized function in humans, but it seemed more likely that LY49L represents an evolutionarily remnant.
In mouse, the Ly49 genes are located in 2 clusters in the natural killer gene complex (NKC) on chromosome 6 (Brown et al., 1997; McQueen et al., 1998). In humans, the NKC is located in a syntenic region on 12p, which also contains the CD94 (KLRD1; 602894), NKRP1 (KLRB1; 602890), and CD69 (107273) genes. By PCR screening of a 22-clone YAC contig, Westgaard et al. (1998) mapped the KLRA1 gene to the human NKC on chromosome 12p13-p12.
NKT cells express both the alpha-beta T cell receptor (TCR; see 186880) and inhibitory MHC-specific NK receptors (NKR; e.g., LY49). Unlike autoreactive T cells, the rare autoreactive NKT cells are not deleted in the thymus but are positively selected upon recognition of CD1D (188410) (with, presumably, an endogenous ligand) expressed by CD4+CD8+ double-positive cortical thymocytes. Deletion of the NKR, or the absence of MHC molecules on target cells, abolishes control of autoreactivity. Using fluorescent CD1D tetramers loaded with the synthetic lipid alpha-galactosylceramide, which uniformly stain all NKT cells expressing the V-alpha-14-J-alpha-18/V-beta-8 TCR, Benlagha et al. (2002) identified, in 2-week-old mice, predominantly CD44-low NK1.1- thymocytes, which mature into CD44-high NK1.1- and then CD44-high NK1.1+ cells. Other NKR such as LY49 are also expressed late in NKT cells. Maturation to the NKR+ stages corresponded with a conversion from production of TH2- (e.g., IL4, 147780) to TH1- (e.g., IFNG, 147570) type cytokines, with an intermediary phase of mixed IL4/IFNG production. Benlagha et al. (2002) suggested that the thymic and postthymic developmental pathways expand autoreactive cells and differentiate them into regulatory cells. In a commentary, MacDonald (2002) proposed a model for the intrathymic development and export of NKT cells.
Desrosiers et al. (2005) used experimental infection with mouse cytomegalovirus (MCMV) to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F2 progeny from MCMV-resistant and MCMV-susceptible mouse strains indicated that only the combination of alleles encoded by a gene in the Klra/Ly49 cluster on mouse chromosome 6, and one in the MHC (H2) on mouse chromosome 17, is associated with virus resistance. These results were suggestive of a new NK cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Klra16/Ly49P receptor and the MHC class I molecule H-2D(k) on MCMV-infected cells.
Barten, R., Trowsdale, J. The human Ly49L gene. Immunogenetics 49: 731-734, 1999. [PubMed: 10369937] [Full Text: https://doi.org/10.1007/s002510050675]
Benlagha, K., Kyin, T., Beavis, A., Teyton, L., Bendelac, A. A thymic precursor to NK T cell lineage. Science 296: 553-555, 2002. [PubMed: 11968185] [Full Text: https://doi.org/10.1126/science.1069017]
Brown, M. G., Fulmek, S., Matsumoto, K., Cho, R., Lyons, P. A., Levy, E. R., Scalzo, A. A., Yokoyama, W. M. A 2-mb yac contig and physical map of the natural killer gene complex on mouse chromosome 6. Genomics 42: 16-25, 1997. [PubMed: 9177771] [Full Text: https://doi.org/10.1006/geno.1997.4721]
Desrosiers, M.-P., Kielczewska, A., Loredo-Osti, J.-C., Adam, S. G., Makrigiannis, A. P., Lemieux, S., Pham, T., Lodoen, M. B., Morgan, K., Lanier, L. L., Vidal, S. M. Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection. Nature Genet. 37: 593-599, 2005. [PubMed: 15895081] [Full Text: https://doi.org/10.1038/ng1564]
MacDonald, H. R. T before NK. Science 296: 481-482, 2002. [PubMed: 11964466] [Full Text: https://doi.org/10.1126/science.1071492]
McQueen, K. L., Freeman, J. D., Takei, F., Mager, D. L. Localization of five new Ly49 genes, including three closely related to Ly49c. Immunogenetics 48: 174-183, 1998. [PubMed: 9683662] [Full Text: https://doi.org/10.1007/s002510050421]
Westgaard, I. H., Berg, S. F., Orstavik, S., Fossum, S., Dissen, E. Identification of a human member of the Ly-49 multigene family. Europ. J. Immun. 28: 1839-1846, 1998. [PubMed: 9645365] [Full Text: https://doi.org/10.1002/(SICI)1521-4141(199806)28:06<1839::AID-IMMU1839>3.0.CO;2-E]