Wolfram syndrome, characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. WFS1 encodes an endoplasmic reticulum resident transmembrane protein with unknown exact function, but its deficiency is shown to affect the unfolded protein response, intracellular Ca2+ homeostasis and granular acidification of secretory granules of pancreatic β-cells (1-3).The aim of the present study was to describe the transcriptome of pancreatic islets of WFS1-deficient mice to find additional genes associated with development of diabetes.RNA of pancreatic islets was extracted from four 5-6 months old male wild-type (WT) mice, heterozygotes for Wfs1 mutation (Wfs1HZ) and homozygotes for Wfs1 mutation (Wfs1KO). For sequencing cDNA was synthesized using Ovation RNA-Seq System V2. The SOLiD 5500xl System and paired end (75 bp forward and 35 bp reverse) chemistry for DNA sequencing was applied. Sequencing reads were mapped to the mouse genome (version mm10) using the LifeScope software. Data were analyzed with the edgeR package implemented in the statistical software R for differential expression. To define the functional networks of the expressed genes, data were run through Ingenuity Pathway Analysis.RNA-sequencing revealed 20 differently expressed genes with false discovery rate (FDR) < 0.05 between Wfs1KO and WT islets (Table 1). Between Wfs1KO and Wfs1HZ 12 genes were expressed differently with FDR<0.05. Functional network analysis of the genes with lowest P-values (after FDR correction) of Wfs1KO compared to WT revealed significant enrichment of a network associated with tissue morphology, molecular transport, endocrine system development and function (score 33, Fig. 1). Analysis of Wfs1KO compared to Wfs1HZ revealed a network associated with cellular development, cellular growth and proliferation, hepatic system development and function (score 28). The most significantly downregulated gene associated with insulin secretion and diabetes in WFS1-deficient islets following Wfs1 was melastatin-related transient receptor potential subfamily member 5 (Trpm5). TRPM5 is expressed in the pancreatic islets of Langerhans, where it regulates the frequency of Ca2+ oscillations and contributes to insulin release from β-cells (5). Although further studies are needed to verify the functional interaction between WFS1 and TRPM5 in the regulation of insulin secretion, RNA-sequencing of pancreatic islets showed that interestingly Trpm5 is downregulated in WFS1-deficient islets, possibly over proinsulin processing. This downregulation may contribute to diabetes-like phenotype of WFS1-deficient mice.