YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
De Franco, E; Lytrivi, M; Ibrahim, H; et al.Montaser, H; Wakeling, M; Fantuzzi, F; Patel, K; Demarez, C; Cai, Y; Igoillo-Esteve, M; Cosentino, C; Lithovius, V; Vihinen, H; Jokitalo, E; Laver, TW; Johnson, MB; Sawatani, T; Shakeri, H; Pachera, N; Haliloglu, B; Ozbek, MN; Unal, E; Yıldırım, R; Godbole, T; Yildiz, M; Aydin, B; Bilheu, A; Suzuki, I; Flanagan, SE; Vanderhaeghen, P; Senée, V; Julier, C; Marchetti, P; Eizirik, DL; Ellard, S; Saarimäki-Vire, J; Otonkoski, T; Cnop, M; Hattersley, AT
Date: 9 November 2020
Journal of Clinical Investigation
American Society for Clinical Investigation
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 ...
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 endoplasmic reticulum (ER)-to-Golgi trafficking. 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 three human β-cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knock-out and mutation knock-in 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-cellsensitivity 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-to65 Golgi trafficking resulting in diabetes.
Institute of Biomedical & Clinical Science
College of Medicine and Health
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Except where otherwise noted, this item's licence is described as © 2020, De Franco et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.