RNA‐sequencing of WFS1‐deficient pancreatic islets

Wolfram syndrome, an autosomal recessive disorder 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. The Wfs1‐null mice exhibit progressive insulin deficiency and diabetes. The aim of this study was to describe the insulin secretion and transcriptome of pancreatic islets in WFS1‐deficient mice. WFS1‐deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild‐type (WT) mice. Wfs1KO pancreatic islets secreted less insulin after incubation in 2 and 10 mmol/L glucose and with tolbutamide solution compared to WT and Wfs1HZ islets, but not after stimulation with 20 mmol/L glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KO had an increased level of proinsulin. After incubation in 2 mmol/L glucose solution the proinsulin/insulin ratio in Wfs1KO was significantly higher than that of WT and Wfs1HZ. RNA‐seq from pancreatic islets found melastatin‐related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated in WFS1‐deficient mice. Functional annotation of RNA sequencing results showed that WFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network.