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

De F., Lytrivi M., Ibrahim H., Montaser H., Wakeling M., Fantuzzi F., ...More

The Journal of clinical investigation, vol.130, pp.6338-6353, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 130
  • Publication Date: 2020
  • Doi Number: 10.1172/jci141455
  • Journal Name: The Journal of clinical investigation
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, CINAHL, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.6338-6353
  • Istanbul University Affiliated: Yes


Neonatal diabetes is caused by single gene mutations reducing pancreatic pcell number or impairing beta cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in beta cells. We identified 6 patients from 5 families with homozygous mutations in the MPS 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 beta cell models (YIPF5 silencing in EndoC-beta H1 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 beta cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and beta cell failure. Partial YIPF5 silencing in EndoC-beta H1 cells and a patient mutation in stem cells increased the beta 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 beta cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.