par De Franco, Elisa;Lytrivi, Maria ;Ibrahim, Hazem;Montaser, Hossam El-dien ;Wakeling, Matthew MN;Fantuzzi, Federica ;Patel, Kashyap A.;Demarez, Céline ;Cai, Ying ;Igoillo Esteve, Mariana ;Cosentino, Cristina ;Lithovius, Väinö;Vihinen, Helena;Jokitalo, Eija;Laver, Thomas W;Johnson, Matthew B;Sawatani, Toshiaki ;Shakeri, Hadis ;Pachera, Nathalie ;Haliloglu, Belma;Ozbek, Mehmet Nuri;Unal, Edip;Yıldırım, Ruken;Godbole, Tushar;Yildiz, Melek;Aydin, Banu;Bilheu, Angeline ;Suzuki, Ikuo ;Flanagan, Sarah E.;Vanderhaeghen, Pierre ;Senée, Valérie;Julier, Cécile;Marchetti, Piero;Eizirik, Decio L. ;Ellard, Sian;Saarimäki-Vire, Jonna;Otonkoski, Timo;Cnop, Miriam ;Hattersley, Andrew T
Référence The Journal of clinical investigation, 130, 12, page (6338-6353)
Publication Publié, 2020-12-01
Référence The Journal of clinical investigation, 130, 12, page (6338-6353)
Publication Publié, 2020-12-01
Article révisé par les pairs
Résumé : | 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. |