Disease relevance of SLC11A1

• OBJECTIVE: The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility [1].
• The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)-negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2 [1].
• Different association studies have shown that the SLC11A1 gene affects susceptibility to infectious diseases and autoimmune inflammatory diseases [2].
• Genetic analysis of SLC11A1 polymorphisms in multiple sclerosis patients [3].
• Association of functional polymorphisms of SLC11A1 with risk of esophageal cancer in the South African Colored population [4].

Psychiatry related information on SLC11A1

• Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease [5].

High impact information on SLC11A1

• This gene is the strongest candidate among the 42 genes in the Idd5.2 region; a naturally occurring mutation in the protective Idd5.2 haplotype results in loss of function of the Nramp1 protein [6].
• In vivo RNA interference demonstrates a role for Nramp1 in modifying susceptibility to type 1 diabetes [6].
• Slc11a1 encodes a phagosomal ion transporter, Nramp1, that affects resistance to intracellular pathogens and influences antigen presentation [6].
• We typed polymorphisms in NRAMP1 in a case-control study of tuberculosis in the Gambia, West Africa. METHODS: Sequence-specific oligonucleotide hybridization and microsatellite analysis were used to type NRAMP1 polymorphisms in 410 adults (mean age, 34.7 years) with smear-positive pulmonary tuberculosis and 417 ethnically matched, healthy controls [7].
• Subjects who were heterozygous for two NRAMP1 polymorphisms in intron 4 and the 3' untranslated region of the gene were particularly overrepresented among those with tuberculosis, as compared with those with the most common NRAMP1 genotype (odds ratio, 4.07; 95 percent confidence interval, 1.86 to 9.12; chi-square= 14.58; P<0.001) [7].

Chemical compound and disease context of SLC11A1

• The NRAMP proteins of Salmonella typhimurium and Escherichia coli are selective manganese transporters involved in the response to reactive oxygen [8].
• The inbred LSH/Se LAK strain of hamster can be infected with Treponema pallidum Bosnia A, the causative agent of endemic syphilis [9].
• A naturally occurring glycine to aspartic acid substitution at position 169 (G169D) within the transmembrane domain 4 (TM4) of Nramp1 makes mice susceptible to Leishmania donovani, Salmonella typhimurium, and Mycobacterium bovis [10].

Biological context of SLC11A1

• Human SLC11A1 mRNA contains an AU-rich element (ARE) within the 3' untranslated region; however, its role in the regulation of SLC11A1 gene expression has not been elucidated [11].
• We also observe that down-regulation of HuR expression by RNA interference (RNAi) results in a decrease in SLC11A1 expression which can be restored by the addition of recombinant HuR protein to the RNAi-treated cells [11].
• Finally, we show that HuR overexpression in HL-60 cells significantly increases the SLC11A1 mRNA stability [11].
• This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9-9.2] versus P = 0.5, OR 1.6 [95% CI 0.4-6.0]) [1].
• Extent and distribution of linkage disequilibrium around the SLC11A1 locus [2].

Anatomical context of SLC11A1

• 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 [12].
• 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 [12].
• Here we report on (1) the physical mapping of NRAMP1 close to VIL in chromosome region 2q35 by PCR analysis of somatic cell hybrids and YAC cloning and (2) the identification of nine sequence variants in NRAMP1 [13].
• Expression and subcellular localization of NRAMP1 in human neutrophil granules [14].
• Finally, immunofluorescence studies of Candida albicans-containing phagosomes formed in neutrophils indicate that NRAMP1 is recruited from tertiary granules to the phagosomal membrane on phagocytosis, supporting a role for NRAMP1 in the antimicrobial defenses of human neutrophils [14].

Associations of SLC11A1 with chemical compounds

• The missense mutations were a conservative alanine-to-valine substitution at codon 318 in exon 9 and an aspartic acid-to-asparagine substitution at codon 543 in the predicted cytoplasmic tail of the NRAMP1 protein [13].
• In macrophages, Nramp1 (Slc11a1) is expressed in lysosomes and restricts replication of intracellular pathogens by removing divalent metals (Mn(2+) and Fe(2+)) from the phagolysosome [15].
• These results identify YGSI as a tyrosine-based sorting signal responsible for lysosomal targeting of Nramp1 [15].
• This lysosomal targeting was abolished by single alanine substitutions at Tyr(15) and Ile(18) of a (15)YGSI(18) motif present in the amino terminus of Nramp1 [15].
• Bacterial lipopolysaccharide or interferon-gamma did not appear to stimulate the level of Nramp expression in PBL [16].

Physical interactions of SLC11A1

• Here we analyze the expression of SLC11A1 in human monocytes and HL-60 cells and then use HL-60 cells as a model to determine whether RNA-binding protein HuR is associated with the ARE and involved in SLC11A1 mRNA turnover [11].
• The membrane topology and transport properties of Nramp1HA and Nramp2HA were indistinguishable, suggesting that Nramp1 divalent-metal transport at the phagosomal membrane is mechanistically similar to that of Nramp2 at the membrane of acidified endosomes [17].
• SLC11 family of H+-coupled metal-ion transporters NRAMP1 and DMT1 [18].

Regulatory relationships of SLC11A1

• In conclusion, NRAMP1 gene promoter polymorphism could influence the radiological severity of rheumatoid arthritis and disease susceptibility, particularly in individuals lacking HLA-linked risk factors [19].
• These data therefore confirm the importance of SLC11A1 in tuberculosis susceptibility in humans and suggest that SLC11A1 influences tuberculosis susceptibility by regulation of interleukin-10 [20].
• Both the reduction in labile iron pool and the up-regulation of HIF-1alpha were suppressed by RNA interference-mediated down-regulation of the iron transporter natural resistance-associated macrophage protein 1 [21].
• The Nramp1 protein is expressed at the phagosomal membrane of macrophages and neutrophils and is a paralog of the Nramp2 (Slc11a2) iron transporter [17].

Other interactions of SLC11A1

• Thus, positive association with SLC11A1 should be interpreted cautiously, and IL8RB should also be considered as a potential candidate susceptibility gene unless proven otherwise [2].
• Our results demonstrate a binding of HuR to the SLC11A1 ARE in phorbol myristate acetate (PMA)-differentiated cells dramatically increased compared to that in undifferentiated cells [11].
• Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well-characterized strong susceptibility to DRB1*08 and *11 alleles [1].
• SLC11A1 regulates macrophage functions that are of potential importance in the induction and/or maintenance of autoimmune diseases such as rheumatoid arthritis, type I diabetes and Crohn's disease [3].
• We found no evidence of association between SLC11A1 polymorphisms and MS susceptibility in the Spanish population [3].

Analytical, diagnostic and therapeutic context of SLC11A1

• Four SLC11A1 gene polymorphisms (5'GT repeat, D543N, 1729 + 55del4 and 1729 + 271del4) were analysed in a case-control study of 195 patients with MS and 125 control subjects [3].
• Functional polymorphism in Z-DNA-forming motif of promoter of SLC11A1 gene and type 1 diabetes in Japanese subjects: association study and meta-analysis [22].
• Stratification by BCG vaccination unmasked a potential genetic risk factor for atopy in the region of the SLC11A1 locus, and point to the importance of genotype by environment interactions in determining disease susceptibility [23].
• Subcellular fractionation of granule populations together with immunoblotting studies with granule-specific markers indicate that NRAMP1 expression is primarily in tertiary granules [14].
• Immunogold studies by cryoelectron microscopy with primary neutrophils confirm that a majority (75%) of NRAMP1-positive granules are also positive for gelatinase, but they also suggest further heterogeneity in this granule population [14].

References