WASHINGTON UNIVERSITY IN ST. LOUIS

Wolfram syndrome was initially categorized as a mitochondrial disease due to the symptoms and several reports reporting the mitochondrial mutations. However, it has been now established that Wolfram syndrome is a prototype of endoplasmic reticulum (ER) disease. Endoplasmic reticulum is a membrane network within our cells that is involved in protein synthesis, calcium storage, redox regulation, steroid synthesis, cell signaling, and cell death. Given the many vital and complex functions of the ER, there is little wonder that its failure can trigger a range of diseases. Previous studies suggest that pancreatic b cells and neurons are particularly sensitive to ER dysfunction. In Wolfram syndrome, pancreatic b cells and neuronal cells are selectively destroyed as a consequence of mutations in the WFS1 gene. This gene encodes a transmembrane protein localized to the ER, suggesting that ER dysfunction is a major pathogenic component of Wolfram syndrome. In Wolfram syndrome, WFS1 mutations..