Abstract
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.
Highlights
Wolfram syndrome (WS, OMIM 222300) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the wolframin gene (WFS1)
The number of pancreatic islets was manually counted during handpicking
When islets were stimulated with 10 mmol/L glucose (Fig. 2) solution, the difference in secreted insulin between WT (0.201 Æ 0.009) and Wfs1KO (0.146 Æ 0.020) was significant (P < 0.05), the difference between Wfs1HZ (0.212 Æ 0.018) and Wfs1KO was highly significant (P < 0.01)
Summary
Wolfram syndrome (WS, OMIM 222300) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the wolframin gene (WFS1). Nonautoimmune degeneration of pancreatic b-cells is common for WS patients (Karasik et al 1989). In patients with WS high levels of endoplasmic reticulum (ER) stress and pancreatic b-cell death may be associated with impaired b-cell function as in the case of type 2 diabetes (T2D) (Fonseca et al 2005). WFS1 is a 100 kDa glycoprotein composed of 890 amino acids and has nine transmembrane segments. Inside the cell WFS1 localizes in the ER (Takeda et al 2001; Hofmann et al 2003; Philbrook et al 2005). Its location in the ER suggests that WFS1 could participate in membrane trafficking, processing proteins and/or regu-
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