β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome

Abstract

Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes.

When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes

“…Another successful patient-derived stem cell endeavor was described, although it recapitulated specifically the phenotype of a rare syndromic form of diabetes known as Wolfram syndrome (MIM222300) [99,104]. Autosomal recessive or compound heterozygous mutations in the wolframin gene, WFS1, which encodes an ER transmembrane protein, give rise to Wolfram syndrome [104].…”

“…The most prominent clinical features of Wolfram syndrome include juvenile insulindependent diabetes, optic atrophy, and deafness [105,106]. Shang and colleagues created insulinproducing C-peptide-positive beta-cells from skin fibroblasts of patients with Wolfram syndrome and control subjects [99]. After differentiation, the mutations in WFS1 inducing the insulin-dependent diabetic phenotype in the Wolfram patients yielded characteristically low insulin content and increased activity of the unfolded protein response (UPR) [99].…”

“…After differentiation, the mutations in WFS1 inducing the insulin-dependent diabetic phenotype in the Wolfram patients yielded characteristically low insulin content and increased activity of the unfolded protein response (UPR) [99]. Upon exposing the cells to the chemical chaperone, 4-phenyl butyric acid (4PBA), UPR pathway activity was reduced and insulin content was adjusted to levels similar to those in control cells, suggesting 4PBA as a novel therapeutic candidate [99]. Moreover, Shang and colleagues performed sophisticated WFS1 locus rescue experiments in patient-derived beta-cells by introducing wild-type WFS1 cDNA via lenti-viral transduction and antibiotic selection of cells expressing stably integrated sequence.…”

“…Shang and colleagues created insulinproducing C-peptide-positive beta-cells from skin fibroblasts of patients with Wolfram syndrome and control subjects [99]. After differentiation, the mutations in WFS1 inducing the insulin-dependent diabetic phenotype in the Wolfram patients yielded characteristically low insulin content and increased activity of the unfolded protein response (UPR) [99]. Upon exposing the cells to the chemical chaperone, 4-phenyl butyric acid (4PBA), UPR pathway activity was reduced and insulin content was adjusted to levels similar to those in control cells, suggesting 4PBA as a novel therapeutic candidate [99].…”

“…The human pancreas remains largely inaccessible, and researchers continue to rely primarily on organ donation and transplantation systems. Therefore, human pancreatic beta-cell lines [96,97] and patient-derived induced pluripotent stem cells (iPS) [98][99][100], are by far the most informative models for studying MODY and the human-specific phenotypic manifestations. Cellular phenotyping in patient-derived iPS cells provides the necessary and highly sought after contextual information (e.g.…”