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    YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
    (American Society for Clinical Investigation, 2020) de Franco, Elisa; Lytrivi, Maria; Ibrahim, Hazem; Montaser, Hossam; Wakeling, Matthew Neil; Fantuzzi, Federica; Patel, Kashyap A.; Demarez, Céline; Cai, Ying; Igoillo-Esteve, Mariana; Cosentino, Cristina; Lithovius, Väinö; Vihinen, Helena; Jokitalo, Eija; Laver, Thomas William; Johnson, Matthew B.; Sawatani, Toshiaki; Shakeri, Hadis; Pachera, Nathalie; Haliloǧlu, Belma; Özbek, Mehmet Nuri; Ünal, Edip; Yıldırım, Ruken; Godbole, Tushar R.; Yıldız, Melek; Aydın, Banu Küçükemre; Bilheu, Angéline; Suzuki, Ikuo K.
    Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell–derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress–induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.