Understanding the multiple functions of Nramp1

Smith

Experimental Eye Research

et al. 2008

Microphthalmia-associated Transcription Factor (Mitf) is expressed in neural crest cell-derived melanocytes, and in the retinal pigment epithelium (RPE) during ocular development. Mutations in Mitf are associated with auditory/visual/pigmentary syndromes in humans. Mitf mi/mi mouse mutants lack pigmentation, and are microphthalmic, while Mitf vit/vit mouse mutants display abnormal RPE pigmentation, and progressive retinal degeneration. Microarray analysis was used to identify novel downstream gene targets/pathways in the RPE that are altered by mutations in the transcription factor Mitf. Using the Affymetrix platform, gene expression profiles were generated using the eyes of E13.5 mouse fetuses that were wildtype, heterozygous, or homozygous for the Mitf mi mutation. In a separate experiment, eyes from E13.5 mouse fetuses homozygous for the Mitf vit mutation were compared to eyes from the C57BL/6 control background strain. Statistical analyses were performed using Robust Multiarray Average, mixed-effects ANOVA and random-variance t-tests. Altered expression of genes involved in pigment formation, melanosome biogenesis/transport, and redox homeostasis were observed. 12 genes were commonly mis-regulated in the eyes of both Mitf mutants: 10 of these genes were downregulated in both mutants relative to controls, while 2 of the genes (Nramp1 (Slc11a1) and epoxide hydrolase) were downregulated in Mitf mi/mi mutants, and conversely, upregulated in Mitf vit/vit mutants. Quantitative RT-PCR and immunohistochemistry were used to confirm altered gene/protein expression. RPE expression of the Fe +2 iron transporter Nramp1 (Slc11a1) has not previously been reported. Fe +2 is an important co-factor utilized by the iron-dependent isomerohydrolase RPE65 in the retinoid visual cycle. However, excess accumulation of Fe +2 in the RPE has recently been associated with oxidative damage and age-related macular degeneration. Abnormal pigmentation and increased activity of Slc11a1 in the RPE of Mitf vit mice may contribute to the pathology and progressive retinal degeneration observed in these mutants.

Section: Discussionmentioning

confidence: 99%

Altered expression of the iron transporter Nramp1 (Slc11a1) during fetal development of the retinal pigment epithelium in microphthalmia-associated transcription factor Mitfmi and Mitfvitiligo mouse mutants

Smith

Experimental Eye Research

et al. 2008

Rev. Soc. Bras. Med. Trop.

“…Assim, também, o gene da proteína 1 associada à resistência natural do macrófago (natural resistance associated macrophage protein 1 -NRAMP1) tem sido relacionado à defesa inata, bem como à adquirida, que confere resistência a parasitas intracelulares, por sua atividade estar diretamente ligada ao processamento dos antígenos bacterianos pelas células fagocitárias 11,12 .…”

Section: Métodosunclassified

Polimorfismos do gene NRAMP1 em indivíduos com reações hansênicas, atendidos em dois Centros de Referência no Recife, nordeste do Brasil

Teixeira

Silva

Ramos

et al. 2010

INTRODUçãO Revista da Sociedade Brasileira de Medicina Tropical 43(3):281-286, mai-jun, 2010Artigo/Article ABSTRACT Introduction:To investigate susceptibility to leprosy reactions, three polymorphisms of the natural resistance-associated macrophage protein (NRAMP1) gene were determined in 201 individuals who were attended at two reference centers in Recife, between 2007 and 2008. Of these, 100 were paucibacillary and 101 were multibacillary. Methods: The 274C/T, D543N and 1729+55del4 polymorphisms of the NRAMP1 gene were determined using the technique of restriction fragment polymorphism on DNA extracted from peripheral blood. Allelic and genotypic frequencies were estimated by direct counting. Results: The predominant genotypes were: CC (51.8%) for 274C/T; GG (86.6%) for D543N; and +-TGTG (59.9%) for 1729+55del4. The mutant genotype 274 TT predominated in negativity of the reverse reaction (p = 0.03) and in positivity of erythema nodosum leprosum (p = 0.04). Conclusions: Our results suggest that 274 C/T polymorphism of the NRAMP1 gene may aid in determining the susceptibility to type II reactions among leprosy patients.

“…This effect on antigen processing is compounded by Slc11a1's influence on molecules regulating (TNF-␣, IL-1␤) or directly involved in (MHC class II) antigen presentation. 15 Hence, in mice vaccinated with attenuated Salmonella typhimurium engineered to express tetanus toxoid fragment C, polarised Th1 vs Th2 responses are observed in Slc11a1 congenic wild-type vs mutant mice. 36 This Th1:Th2 bias is also seen in mycobacterial infection in Slc11a1 congenic mice.…”

Section: Introductionmentioning

confidence: 96%

“…In mice, Slc11a1 controls response to Mycobacterium bovis BCG, as well as to a range of other intracellular macrophage pathogens (reviewed in Blackwell et al 15 ). In man, SLC11A1 has been shown to be linked or associated with both infectious [16][17][18][19][20][21][22][23] and autoimmune [24][25][26][27][28][29][30] diseases.…”

Section: Introductionmentioning

confidence: 99%

“…The protein encoded by Slc11a1/SLC11A1 localizes to membranes of late endosome/lysosomes, 31,32 and is a proton/divalent cation antiporter. 33 Whilst divalent cation transport may directly affect antimicrobial activity through contribution of Fe 2+ to the Fenton Reaction, 34 the central role of divalent cations in many cellular functions provides the basis to multiple pleiotropic effects of the SLC11A1 gene (reviewed in Blackwell et al 15 ). One such pleiotropic effect is enhanced antigen processing for presentation to T cells, 35 which may reflect metal ion requirement for metalloprotease activity and/or endosomal fusion events.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Atopy in children in relation to BCG vaccination and genetic polymorphisms at SLC11A1 (formerly NRAMP1) and D2S1471

et al. 2002