Beta cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome

  1. Dieter Egli1,*
  1. 1The New York Stem Cell Foundation Laboratory, New York, NY 10032, USA
  2. 2Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA
  1. *Corresponding Author: Dieter Egli, E-mail: d.egli{at}


Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and characterized by insulin-dependent diabetes mellitus, optic atrophy and deafness. To investigate the cause of beta cell failure, we used induced pluripotent stem (iPS) cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient beta cells showed increased levels of endoplasmic reticulum (ER) stress molecules, and decreased insulin content. Upon exposure to experimental ER stress, Wolfram beta 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 beta 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.

  • Received May 3, 2013.
  • Accepted November 4, 2013.

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