YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

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 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.