Nature Genetics 38, 479 - 483 (2006)
Published online: 19 March 2006; | doi:10.1038/ng1766
In vivo RNA interference demonstrates a role for Nramp1 in modifying susceptibility to type 1 diabetesStephan Kissler1, 5, Patrick Stern1, 5, Kazue Takahashi2, Kara Hunter3, Laurence B Peterson4
& Linda S Wicker31
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. 2
Laboratory of Developmental Immunology, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts 02114, USA. 3
Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, UK. 4
Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065, USA. 5
These authors contributed equally to this work.
Correspondence should be addressed to Stephan Kissler skissler@mit.edu Type 1 diabetes is an autoimmune disease influenced by multiple genetic loci. Although more than 20 insulin-dependent diabetes (Idd) loci have been implicated in the nonobese diabetic (NOD) mouse model1,
2, few causal gene variants have been identified3,
4. Here we show that RNA interference5,
6 (RNAi) can be used to probe candidate genes in this disease model. Slc11a1 encodes a phagosomal ion transporter, Nramp1, that affects resistance to intracellular pathogens and influences antigen presentation7,
8,
9. 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 protein10. Using lentiviral transgenesis11, we generated NOD mice in which Slc11a1 is silenced by RNAi. Silencing reduced the frequency of type 1 diabetes, mimicking the protective Idd5.2 region. Our results demonstrate a role for Slc11a1 in modifying susceptibility to type 1 diabetes and illustrate that RNAi can be used to study causal genes in a mammalian model organism.
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