YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
De Franco, Elisa
Wakeling, M. N.
Hattersley, Andrew T.
Laver, T. W.
Johnson, M. B.
JournalThe Journal of Clinical Invesitigation
PublisherAmerican Society for Clinical Investigation
Rights© 2020, De Franco et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License
CC0 1.0 Universal
MetadataShow full item record
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.
CitationDe Franco E et al. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. J Clin Invest. 2020 Dec 1;130(12):6338-6353.
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