Type 1 diabetes in mice and men gene expression p

Authors: Linda Yip C Garrison Fathman

Publish Date: 2014/03/29

Volume: 58, Issue: 2-3, Pages: 340-350

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Abstract

Type 1 diabetes T1D is a complex polygenic disease that is triggered by various environmental factors in genetically susceptible individuals The emphasis placed on genomewide association studies to explain the genetics of T1D has failed to advance our understanding of T1D pathogenesis or identify biomarkers of disease progression or therapeutic targets Using the nonobese diabetic NOD mouse model of T1D and the nondisease prone congenic NODB10 mice our laboratory demonstrated striking tissuespecific and agedependent changes in gene expression during disease progression We established a “roadmap” of differential gene expression and used this to identify candidate genes in mice and human orthologs that play a role in disease pathology Here we describe two genes Deformed epidermal autoregulatory factor 1 Deaf1 and Adenosine A1 receptor Adora1 that are differentially expressed and alternatively spliced in the pancreatic lymph nodes or islets of NOD mice and T1D patients to form dominantnegative nonfunctional isoforms Loss of Deaf1 function leads to reduced peripheral tissue antigen expression in lymph node stromal cells and may contribute to a breakdown in peripheral tolerance while reduced Adora1 function results in an early intrinsic alpha cell defect that may explain the hyperglucagonemia and resulting beta cell stress observed prior to the onset of diabetes Remarkably both genes were also alternatively spliced in the same tissues of autoantibody positive prediabetic patients and these splicing events resulted in similar downstream effects as those seen in NOD mice These findings demonstrate the value of gene expression profiling in studying disease pathogenesis in T1DThe work presented was funded by NIH grants DK078123 and AI083628 and performed with the support of the Network for Pancreatic Organ Donors with Diabetes nPOD a collaborative type 1 diabetes research project sponsored by JDRF Organ Procurement Organizations OPO partnering with nPOD to provide research resources are listed at http//wwwjdrfnpodorg/forpartners/npodpartners Linda Yip was supported by the JDRF Transition Award

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