title: RNA-sequencing of WFS1-deficient pancreatic islets.
abstract: Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in theWFS1gene.WFS1encodes an endoplasmic reticulum resident transmembrane protein. TheWfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of this study was to describe the insulin secretion and transcriptome of pancreatic islets inWFS1-deficient mice.WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KOpancreatic islets secreted less insulin after incubation in 2 and 10 mmol/L glucose and with tolbutamide solution compared toWTand Wfs1HZislets, but not after stimulation with 20 mmol/L glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KOhad an increased level of proinsulin. After incubation in 2 mmol/L glucose solution the proinsulin/insulin ratio in Wfs1KOwas significantly higher than that ofWTand Wfs1HZRNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated inWFS1-deficient mice. Functional annotation ofRNAsequencing results showed thatWFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network.
authors.affiliation: Department of Pathophysiology, Institute of Biomedicine and Translational Medicine University of Tartu, Tartu, Estonia marilin.ivask@ut.ee.
authors.forename: Marilin
authors.initials: M
authors.lastname: Ivask
authors.affiliation: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Hugill
authors.affiliation: Department of Pathophysiology, Institute of Biomedicine and Translational Medicine University of Tartu, Tartu, Estonia.
authors.forename: Sulev
authors.initials: S
authors.lastname: Kõks
mesh_terms: D000818:Animals; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000494:pharmacology; D006579:Heterozygote; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011384:Proinsulin / Q000378:metabolism; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D014044:Tolbutamide / Q000494:pharmacology; D014158:Transcription, Genetic; D059467:Transcriptome; D014929:Wolfram Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D008565:Membrane Proteins; D050053:TRPM Cation Channels; C498617:Trpm5 protein, mouse; C114987:wolframin protein; D012313:RNA; D011384:Proinsulin; D014044:Tolbutamide; D005947:Glucose
keywords: Insulin; RNA‐sequencing; Trpm5; Wfs1