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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 model, few causal gene variants have been identified. Here we show that RNA interference (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 presentation. 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. Using lentiviral transgenesis, 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.

Original publication

DOI

10.1038/ng1766

Type

Journal article

Journal

Nature genetics

Publication Date

04/2006

Volume

38

Pages

479 - 483

Addresses

Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. skissler@mit.edu

Keywords

Animals, Mice, Inbred NOD, Mice, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Cation Transport Proteins, RNA Interference, Female, Male