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.

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

Marchetti P.;
2020-01-01

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 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.
2020
de Franco, E.; Lytrivi, M.; Ibrahim, H.; Montaser, H.; Wakeling, M. N.; Fantuzzi, F.; Patel, K.; Demarez, C.; Cai, Y.; Igoillo-Esteve, M.; Cosentino, C.; Lithovius, V.; Vihinen, H.; Jokitalo, E.; Laver, T. W.; Johnson, M. B.; Sawatani, T.; Shakeri, H.; Pachera, N.; Haliloglu, B.; Ozbek, M. N.; Unal, E.; Yildirim, R.; Godbole, T.; Yildiz, M.; Aydin, B.; Bilheu, A.; Suzuki, I.; Flanagan, S. E.; Vanderhaeghen, P.; Senee, V.; Julier, C.; Marchetti, P.; Eizirik, D. L.; Ellard, S.; Saarimaki-Vire, J.; Otonkoski, T.; Cnop, M.; Hattersley, A. T.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1076147
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