WFS1 encodes wolframin, an endoplasmic reticulum (ER) membrane glycoprotein that plays critical roles in cellular calcium homeostasis and ER stress regulation 1. The protein participates in regulating cellular Ca2+ homeostasis by modulating ER calcium store filling and negatively regulates ER stress responses 1. WFS1 is essential for mitochondria-associated ER membrane (MAM) integrity and functionality, facilitating ER-to-mitochondria calcium transfer 2. Loss of WFS1 function results in reduced mitochondrial calcium uptake, bioenergetic dysfunction, and enhanced autophagy and mitophagy 2. In pancreatic β cells, WFS1 deficiency leads to cellular dedifferentiation and loss of insulin-producing capacity through mechanisms involving decreased ATP content and impaired oxidative glycolysis 3. Mutations in WFS1 cause a spectrum of disorders ranging from severe autosomal recessive Wolfram syndrome (characterized by diabetes, optic atrophy, deafness, and diabetes insipidus) to milder autosomal dominant Wolfram-like syndrome 4. The protein's dysfunction contributes to β cell failure in diabetes through ER stress-mediated pathways, with biallelic loss-of-function variants predicting full Wolfram syndrome with high specificity 5. WFS1-related diabetes is often misdiagnosed and requires genetic testing for proper identification and individualized treatment 6.