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J Exp Med. Nov 1, 1994; 180(5): 1741–1752.
PMCID: PMC2191750

Human natural resistance-associated macrophage protein: cDNA cloning, chromosomal mapping, genomic organization, and tissue-specific expression

Abstract

Natural resistance to infection with unrelated intracellular parasites such as Mycobacteria, Salmonella, and Leishmania is controlled in the mouse by a single gene on chromosome 1, designated Bcg, Ity, or Lsh. A candidate gene for Bcg, designated natural resistance-associated macrophage protein (Nramp), has been isolated and shown to encode a novel macrophage-specific membrane protein, which is altered in susceptible animals. We have cloned and characterized cDNA clones corresponding to the human NRAMP gene. Nucleotide and predicted amino acid sequence analyses indicate that the human NRAMP polypeptide encodes a 550-amino acid residue membrane protein with 10-12 putative transmembrane domains, two N-linked glycosylation sites, and an evolutionary conserved consensus transport motif. Identification of genomic clones corresponding to human NRAMP indicates that the gene maps to chromosome 2q35 within a group of syntenic loci conserved with proximal mouse 1. The gene is composed of at least 15 exons, with several exons encoding discrete predicted structural domains of the protein. These studies have also identified an alternatively spliced exon encoded by an Alu element present within intron 4. Although this novel exon was found expressed in vivo, it would introduce a termination codon in the downstream exon V, resulting in a severely truncated protein. Northern blot analyses indicate that NRAMP mRNA expression is tightly controlled in a tissue-specific fashion, with the highest sites of expression being peripheral blood leukocytes, lungs, and spleen. Additional RNA expression studies in cultured cells identified the macrophage as a site of expression of human NRAMP and indicated that increased expression was correlated with an advanced state of differentiation of this lineage.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bloom BR. Tuberculosis. Back to a frightening future. Nature. 1992 Aug 13;358(6387):538–539. [PubMed]
  • Stead WW. Genetics and resistance to tuberculosis. Could resistance be enhanced by genetic engineering? Ann Intern Med. 1992 Jun 1;116(11):937–941. [PubMed]
  • Crowle AJ, Elkins N. Relative permissiveness of macrophages from black and white people for virulent tubercle bacilli. Infect Immun. 1990 Mar;58(3):632–638. [PMC free article] [PubMed]
  • Schurr E, Malo D, Radzioch D, Buschman E, Morgan K, Gros P, Skamene E. Genetic control of innate resistance to mycobacterial infections. Immunol Today. 1991 Mar;12(3):A42–A45. [PubMed]
  • Schurr E, Morgan K, Gros P, Skamene E. Genetics of leprosy. Am J Trop Med Hyg. 1991 Apr;44(4 Pt 2):4–11. [PubMed]
  • Skamene E, Gros P, Forget A, Patel PJ, Nesbitt MN. Regulation of resistance to leprosy by chromosome 1 locus in the mouse. Immunogenetics. 1984;19(2):117–124. [PubMed]
  • Goto Y, Buschman E, Skamene E. Regulation of host resistance to Mycobacterium intracellulare in vivo and in vitro by the Bcg gene. Immunogenetics. 1989;30(3):218–221. [PubMed]
  • Gros P, Skamene E, Forget A. Genetic control of natural resistance to Mycobacterium bovis (BCG) in mice. J Immunol. 1981 Dec;127(6):2417–2421. [PubMed]
  • Gros P, Skamene E, Forget A. Cellular mechanisms of genetically controlled host resistance to Mycobacterium bovis (BCG). J Immunol. 1983 Oct;131(4):1966–1972. [PubMed]
  • Plant J, Glynn AA. Genetics of resistance to infection with Salmonella typhimurium in mice. J Infect Dis. 1976 Jan;133(1):72–78. [PubMed]
  • Bradley DJ. Regulation of Leishmania populations within the host. II. genetic control of acute susceptibility of mice to Leishmania donovani infection. Clin Exp Immunol. 1977 Oct;30(1):130–140. [PMC free article] [PubMed]
  • Skamene E, Gros P, Forget A, Kongshavn PA, St Charles C, Taylor BA. Genetic regulation of resistance to intracellular pathogens. Nature. 1982 Jun 10;297(5866):506–509. [PubMed]
  • Malo D, Vidal SM, Hu J, Skamene E, Gros P. High-resolution linkage map in the vicinity of the host resistance locus Bcg. Genomics. 1993 Jun;16(3):655–663. [PubMed]
  • Malo D, Vidal S, Lieman JH, Ward DC, Gros P. Physical delineation of the minimal chromosomal segment encompassing the murine host resistance locus Bcg. Genomics. 1993 Sep;17(3):667–675. [PubMed]
  • Vidal SM, Malo D, Vogan K, Skamene E, Gros P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell. 1993 May 7;73(3):469–485. [PubMed]
  • Kerppola RE, Ames GF. Topology of the hydrophobic membrane-bound components of the histidine periplasmic permease. Comparison with other members of the family. J Biol Chem. 1992 Feb 5;267(4):2329–2336. [PubMed]
  • Bairoch A. PROSITE: a dictionary of sites and patterns in proteins. Nucleic Acids Res. 1991 Apr 25;19 (Suppl):2241–2245. [PMC free article] [PubMed]
  • Unkles SE, Hawker KL, Grieve C, Campbell EI, Montague P, Kinghorn JR. crnA encodes a nitrate transporter in Aspergillus nidulans. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):204–208. [PMC free article] [PubMed]
  • Stuehr DJ, Nathan CF. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. [PMC free article] [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Epstein DJ, Vekemans M, Gros P. Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell. 1991 Nov 15;67(4):767–774. [PubMed]
  • Noonan KE, Roninson IB. mRNA phenotyping by enzymatic amplification of randomly primed cDNA. Nucleic Acids Res. 1988 Nov 11;16(21):10366–10366. [PMC free article] [PubMed]
  • Mangalan H. Striding the turf of the gang of four. Trends Biochem Sci. 1993 May;18(5):187–188. [PubMed]
  • Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Schurr E, Skamene E, Morgan K, Chu ML, Gros P. Mapping of Col3a1 and Col6a3 to proximal murine chromosome 1 identifies conserved linkage of structural protein genes between murine chromosome 1 and human chromosome 2q. Genomics. 1990 Nov;8(3):477–486. [PubMed]
  • Rousseau-Merck MF, Simon-Chazottes D, Arpin M, Pringault E, Louvard D, Guénet JL, Berger R. Localization of the villin gene on human chromosome 2q35-q36 and on mouse chromosome 1. Hum Genet. 1988 Feb;78(2):130–133. [PubMed]
  • Mount SM. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. [PMC free article] [PubMed]
  • Jurka J, Milosavljevic A. Reconstruction and analysis of human Alu genes. J Mol Evol. 1991 Feb;32(2):105–121. [PubMed]
  • Caras IW, Davitz MA, Rhee L, Weddell G, Martin DW, Jr, Nussenzweig V. Cloning of decay-accelerating factor suggests novel use of splicing to generate two proteins. Nature. 1987 Feb 5;325(6104):545–549. [PubMed]
  • Languino LR, Ruoslahti E. An alternative form of the integrin beta 1 subunit with a variant cytoplasmic domain. J Biol Chem. 1992 Apr 5;267(10):7116–7120. [PubMed]
  • Wong P, MacDonald IM, Sood R, Smith C, Pilon R, Tenniswood M. Identification and partial characterization of a candidate gene for X-linked retinopathies using a lateral approach. Genomics. 1993 Mar;15(3):467–471. [PubMed]
  • Lübbert M, Herrmann F, Koeffler HP. Expression and regulation of myeloid-specific genes in normal and leukemic myeloid cells. Blood. 1991 Mar 1;77(5):909–924. [PubMed]
  • Barton CH, White JK, Roach TI, Blackwell JM. NH2-terminal sequence of macrophage-expressed natural resistance-associated macrophage protein (Nramp) encodes a proline/serine-rich putative Src homology 3-binding domain. J Exp Med. 1994 May 1;179(5):1683–1687. [PMC free article] [PubMed]
  • Kyte J, Doolittle RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. [PubMed]
  • Eisenberg D, Schwarz E, Komaromy M, Wall R. Analysis of membrane and surface protein sequences with the hydrophobic moment plot. J Mol Biol. 1984 Oct 15;179(1):125–142. [PubMed]
  • Boguski MS, Lowe TM, Tolstoshev CM. dbEST--database for "expressed sequence tags". Nat Genet. 1993 Aug;4(4):332–333. [PubMed]
  • Nathans J, Hogness DS. Isolation, sequence analysis, and intron-exon arrangement of the gene encoding bovine rhodopsin. Cell. 1983 Oct;34(3):807–814. [PubMed]
  • Britten RJ, Baron WF, Stout DB, Davidson EH. Sources and evolution of human Alu repeated sequences. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4770–4774. [PMC free article] [PubMed]
  • Rutherford MS, Witsell A, Schook LB. Mechanisms generating functionally heterogeneous macrophages: chaos revisited. J Leukoc Biol. 1993 May;53(5):602–618. [PubMed]
  • Schneemann M, Schoedon G, Hofer S, Blau N, Guerrero L, Schaffner A. Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes. J Infect Dis. 1993 Jun;167(6):1358–1363. [PubMed]
  • Kolb JP, Paul-Eugene N, Damais C, Yamaoka K, Drapier JC, Dugas B. Interleukin-4 stimulates cGMP production by IFN-gamma-activated human monocytes. Involvement of the nitric oxide synthase pathway. J Biol Chem. 1994 Apr 1;269(13):9811–9816. [PubMed]
  • Lowenstein CJ, Alley EW, Raval P, Snowman AM, Snyder SH, Russell SW, Murphy WJ. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9730–9734. [PMC free article] [PubMed]

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