B6J.129S1-Slc11a1^r/GbrtJ

Stock number: 027081
Research areas: Cell Biology Research, Immunology, Inflammation and Autoimmunity Research, Metabolism Research

Description

This C57BL/6J congenic strain, commonly called Nramp1^r/r, may be useful to further study the role of the ion transporter Nramp1 in mycobacterial infections.

Detailed description

This C57BL/6J congenic strain, commonly called Nramp1^r/r, contain a genomic segment from the mycobacteria resistant 129S1 background introgressed into Chromosome 1. This segment contains Slc11a1, solute carrier family 11 (proton-coupled divalent metal ion transporters), member 1, also known as Nramp1 (natural-resistance-associated macrophage protein 1) or the Bcg/Ity/Lsh locus. NRAMP1 is a membrane protein expressed on macrophages that acts as a divalent transition metal (iron and manganese) transporter involved in iron metabolism and host resistance to certain pathogens. Mutations, resulting in a non-functional protein, have been associated with the innate susceptibility of mice to infection with a group of unrelated intracellular parasites which includes Mycobacterium bovis, Salmonella typhimurium, and Leishmania donovani. The lack of functionality causes an accumulation of ions inside the phagosome, favoring the replication of the pathogens. This strain contains a 129S1-derived natural resistance mutation in the Slc11a1 gene backcrossed onto the infection susceptible C57BL/6J background. A guanine at nucleotide position 783 produces a protein with Glycine at position 105 within the second predicted transmembrane domain. The protein also has Glycine at position 169 within the fourth predicted transmembrane domain. Nramp1^r/r mice are resistant to infection by mycobacterial infections.

Development

This C57BL/6J congenic strain contains a genomic segment from the mycobacteria resistant 129S1 background introgressed into Chromosome 1. The chromosome 1 genomic segment from 129 contains Slc11a1, solute carrier family 11 (proton-coupled divalent metal ion transporters), member 1 (74.3Mb). A guanine mutation at nucleotide position 783 produces a protein with Glycine at position 105 within the second predicted transmembrane domain. The protein also has Glycine at position 169 within the fourth predicted transmembrane domain. The 129S1 genomic segment was transferred through 12 generations of backcrossing to C57BL/6J. Siblings carrying the 129S1 derived segments were intercrossed to make homozygous.

Allele

Symbol: Slc11a1^r
Name: host resistance (Bcg/Ity/Lsh)
MGI accession ID: MGI:1857756
Generation method: Not Applicable
Marker symbol: Slc11a1
Marker name: solute carrier family 11 (proton-coupled divalent metal ion transporters), member 1
Chromosome: 1
Strain of origin: multiple strains
Molecular note: Natural resistance to infection with diverse pathogens, including some Mycobacterium species, Salmonella typhimurium, and Leishmania donovani, is associated with a protein having glycine at amino acid position 169, within the fourth predicted transmembrane domain (G169 or Gly169). This glycine is evolutionarily conserved in rat, human, rabbit and chicken orthologous proteins. G169 is associated with the G variant of SNP rs47476426 and is found in 129P2/OlaHsd, 129S1/SvImJ, 129S5SvEvBrd, C3H/HeJ and most other strains. Reference strain C57BL/6, and BALB/cJ and FVB/NJ have the A variant of the SNP, coding for aspartic acid at position 169, that causes sensitivity.
General note: Multiple genes may be involved in the control of mycobacterial infections in inbred mice (J:17780); the early phase of these infections is controlled in Slc11a1^r strains, but later phases are not (J:28278).

The point mutation associated with the susceptible phenotype (Slc11a1^s) was initially identified as Gly105Arg. In J:25627 (1995), the authors report that the full-length mRNA encodes a protein 64 amino acids longer at the N-terminus than previously reported, including two additional transmembrane domains. Therefore, the actual amino acid substitution is Gly169Arg, and the resistant allele Gly169 (or G169). The nucleotides cannot be assigned numbers because the gene contains no TATA or CAAT element and has multiple transcription initiation sites. (J:25627)

Resistant strains include 129S4/SvJae, 129X1/SvJ, A/J, AKR/J, BUB/BnJ, C3H/HeJ, C57BR/cdJ, C57L/J, C58/J, CBA/J, DBA/2J, LP/J, NOD/ShiLt, NZB/BlNJ, P/J, PL/J, RIIIS/J, RF/J, SJL/J, SWR/J, Mus spretus (Spain). (J:4762, J:20139) Some of these strains carry silent nucleotide substitutions. (J:20139)