TY - JOUR TI - EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence AU - Gautheron, Jeremie AU - Morisseau, Christophe AU - Chung, Wendy K AU - Zammouri, Jamila AU - Auclair, Martine AU - Baujat, Genevieve AU - Capel, Emilie AU - Moulin, Celia AU - Wang, Yuxin AU - Yang, Jun AU - Hammock, Bruce D AU - Cerame, Barbara AU - Phan, Franck AU - Fève, Bruno AU - Vigouroux, Corinne AU - Andreelli, Fabrizio AU - Jeru, Isabelle A2 - Czech, Michael A2 - James, David E A2 - Semple, Robert VL - 10 PY - 2021 DA - 2021/08/03 SP - e68445 C1 - eLife 2021;10:e68445 DO - 10.7554/eLife.68445 UR - https://doi.org/10.7554/eLife.68445 AB - Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans. KW - diabetes KW - genetics KW - epoxide hydrolase KW - adipocyte KW - cellular senescence KW - EPHX1 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -