YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.
In: Journal of Clinical Investigation, Jg. 130 (2020-12-01), Heft 12, S. 6338-6353
Online
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Zugriff:
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. [ABSTRACT FROM AUTHOR]
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YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.
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Autor/in / Beteiligte Person: | Franco, Elisa De ; Lytrivi, Maria ; Ibrahim, Hazem ; Montaser, Hossam ; Wakeling, Matthew N. ; Fantuzzi, Federica ; Patel, Kashyap ; Demarez, Céline ; Cai, Ying ; Igoillo-Esteve, Mariana ; Cosentino, Cristina ; Lithovius, Väinö ; Vihinen, Helena ; Jokitalo, Eija ; Laver, Thomas W. ; Johnson, Matthew B. ; Sawatani, Toshiaki ; Shakeri, Hadis ; Pachera, Nathalie ; Haliloglu, Belma |
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Zeitschrift: | Journal of Clinical Investigation, Jg. 130 (2020-12-01), Heft 12, S. 6338-6353 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
ISSN: | 0021-9738 (print) |
DOI: | 10.1172/JCI141455 |
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