YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.

ABSTRACT

Neonatal diabetes is caused by single gene mutations reducing pancreatic ß cell number or impairing ß cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in ß 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 ß cell models (YIPF5 silencing in EndoC-ßH1 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 ß cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and ß cell failure. Partial YIPF5 silencing in EndoC-ßH1 cells and a patient mutation in stem cells increased the ß 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 ß cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.