WFS1

The protein regulates cellular calcium homeostasis by modulating endoplasmic reticulum calcium stores and negatively regulates the ER stress response. Mutations cause Wolfram syndrome (autosomal recessive), a multisystem disorder affecting the brain, central nervous system, pancreas, and eyes with features including diabetes mellitus, optic atrophy, diabetes insipidus, and deafness, as well as autosomal dominant deafness. The gene shows very low constraint to loss-of-function mutations (high LOEUF score), consistent with its recessive inheritance pattern for the severe multisystem phenotype.