|Coordinate||57,402,811 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||adhesion G protein-coupled receptor E1|
|Synonym(s)||Emr1, EGF-TM7, F4/80, DD7A5-7, TM7LN3, Ly71|
|Chromosomal Location||57,358,686-57,483,529 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a protein that has a domain resembling seven transmembrane G protein-coupled hormone receptors (7TM receptors) at its C-terminus. The N-terminus of the encoded protein has six EGF-like modules, separated from the transmembrane segments by a serine/threonine-rich domain, a feature reminiscent of mucin-like, single-span, integral membrane glycoproteins with adhesive properties. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]
PHENOTYPE: Homozygous null mice fail to develop peripheral tolerance after inoculation with antigen because of a lack of efferent regulatory T cell development. [provided by MGI curators]
|Amino Acid Change||Tyrosine changed to Cysteine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000004850] [ENSMUSP00000083971]|
AA Change: Y156C
AA Change: Y156C
|Meta Mutation Damage Score||0.4177|
|Is this an essential gene?||Probably nonessential (E-score: 0.158)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.438; ML prob: 0.438; human score: 2.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2021-11-01 7:45 AM by Diantha La Vine|
|Record Created||2016-02-28 10:07 AM by Bruce Beutler|
The lomax phenotype was initially identified among G3 mice of the pedigree R4190, some of which showed a reduction in the frequency of F4/80+ macrophages in the peripheral blood (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 47 mutations. The reduction in frequency of F4/80+ macrophages was linked by continuous variable mapping to a mutation in Emr1 (alternatively, Adgre1): an A to G transition at base pair 57,402,811 (v38) on chromosome 17, or base pair 44,161 in the GenBank genomic region NC_000083 encoding Emr1. Linkage was found with a recessive model of inheritance (P = 1.284 x 10-6), wherein 4 variant homozygous departed phenotypically from 16 homozygous reference mice and 20 heterozygous mice (Figure 2).
The mutation corresponds to residue 507 in the mRNA sequence NM_010130 within exon 5 of 22 total exons.
The mutated nucleotide is indicated in red. The mutation results in a tyrosine (Y) to cysteine (C) substitution at position 156 (Y156C) in the F4/80 protein.
|Illustration of Mutations in
Gene & Protein
Emr1 encodes the F4/80 glycoprotein, which is a cell surface receptor that contains seven transmembrane (TM7) domains (Figure 3). F4/80 is a member of the B2 class of TM7 receptors, which are characterized by a long N-terminal extracellular region. Following a signal peptide, the extracellular N-terminal third of F4/80 (amino acids 32-367) contains seven tandem EGF-like domains (1), approximately 50 amino acids in length and characterized by the presence of six cysteine residues positioned to form three disulfide bonds within each domain. The EGF-like domains mediate protein-protein interactions. Five of the seven EGF-like domains of F4/80 contain consensus Ca2+-binding motifs. The C-terminal third of F4/80 (amino acids ~645-931) contains seven transmembrane segments, three extracellular loops, and three intracellular loops, with the C-terminus of the protein located intracellularly. Between the EGF-like domains at the N-terminus and the TM7 structure at the C-terminus, the middle third, or stalk region, of F4/80 has no significant similarity to other known protein domains. This portion of the protein (amino acids ~399-642) contains 4 potential N-glycosylation sites and 47 potential O-glycosylation sites (i.e. approximately 20% serine/threonine content). The lomax mutation results in substitution of tyrosine 156 to a cysteine; amino acid 156 is within the extracellular N-terminal tail of F4/80 (amino acids 32-367), more specifically within the third EGF-like domain (amino acids 133-172).
Please see the record for F4/80 for more information about Emr1.
F4/80 is best known as a macrophage-specific marker. The physiological function of F4/80 has only begun to be investigated, and evidence of its function remains sparse. F4/80-/- mice are healthy and fertile, and display no gross abnormalities or phenotypes (2;3). Histological analysis showed that immune tissues appear normal, and flow cytometric analysis demonstrated normal populations of B and T cells. Furthermore, F4/80-/- macrophage development, as determined by examination of expression profiles of several macrophage-restricted cell surface proteins, is comparable to that of wild type mice. F4/80-/- macrophages phagocytose target cells normally, and produce normal levels of nitric oxide and cytokines stimulated by lipopolysaccharide (LPS) or IFN-γ (2). F4/80-/- mice (and the ENU-induced Emr1F4/80/F4/80 mutants) also display normal resistance to infection by Listeria monocytogenes (3). This finding contrasts with previous work demonstrating that treatment with anti-F4/80 mAb impairs splenic macrophage production of tumor necrosis factor (TNF)-α and interleukin (IL)-12 induced by exposure to heat-killed Listeria (4). However, whether Listeria infection modulates the expression of F4/80 is unknown, as is the molecular effect of anti-F4/80 mAb treatment on cells. F4/80 protein and mRNA expression have not been examined in lomax mice; however, the lomax mutation is proposed to alter the protein-protein interactions between F4/80 and an unidentified protein, subsequently leading to the phenotype observed in the FACS screen.
1) 94°C 2:00
The following sequence of 435 nucleotides is amplified (chromosome 17, + strand):
1 agtttggata attttctctg cgcaggtaat atcctcaggc tctctgccac aggtctttgg
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. McKnight, A. J., Macfarlane, A. J., Dri, P., Turley, L., Willis, A. C., and Gordon, S. (1996) Molecular Cloning of F4/80, a Murine Macrophage-Restricted Cell Surface Glycoprotein with Homology to the G-Protein-Linked Transmembrane 7 Hormone Receptor Family. J Biol Chem. 271, 486-489.
2. Lin, H. H., Faunce, D. E., Stacey, M., Terajewicz, A., Nakamura, T., Zhang-Hoover, J., Kerley, M., Mucenski, M. L., Gordon, S., and Stein-Streilein, J. (2005) The Macrophage F4/80 Receptor is Required for the Induction of Antigen-Specific Efferent Regulatory T Cells in Peripheral Tolerance. J Exp Med. 201, 1615-1625.
3. Schaller, E., Macfarlane, A. J., Rupec, R. A., Gordon, S., McKnight, A. J., and Pfeffer, K. (2002) Inactivation of the F4/80 Glycoprotein in the Mouse Germ Line. Mol Cell Biol. 22, 8035-8043.
|Science Writers||Anne Murray|
|Authors||Xue Zhong, Ming Zeng, and Bruce Beutler|