YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

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Abstract

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.

Authors

Elisa De Franco, Maria Lytrivi, Hazem Ibrahim, Hossam Montaser, Matthew N. Wakeling, Federica Fantuzzi, Kashyap Patel, Céline Demarez, Ying Cai, Mariana Igoillo-Esteve, Cristina Cosentino, Väinö Lithovius, Helena Vihinen, Eija Jokitalo, Thomas W. Laver, Matthew B. Johnson, Toshiaki Sawatani, Hadis Shakeri, Nathalie Pachera, Belma Haliloglu, Mehmet Nuri Ozbek, Edip Unal, Ruken Yıldırım, Tushar Godbole, Melek Yildiz, Banu Aydin, Angeline Bilheu, Ikuo Suzuki, Sarah E. Flanagan, Pierre Vanderhaeghen, Valérie Senée, Cécile Julier, Piero Marchetti, Decio L. Eizirik, Sian Ellard, Jonna Saarimäki-Vire, Timo Otonkoski, Miriam Cnop, Andrew T. Hattersley