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YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

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info:eu-repo/semantics/openAccess

Date

2020

Author

de Franco, Elisa
Lytrivi, Maria
Ibrahim, Hazem
Montaser, Hossam
Wakeling, Matthew Neil
Fantuzzi, Federica
Patel, Kashyap A.
Demarez, Céline
Cai, Ying
Igoillo-Esteve, Mariana
Cosentino, Cristina
Lithovius, Väinö
Vihinen, Helena
Jokitalo, Eija
Laver, Thomas William
Johnson, Matthew B.
Sawatani, Toshiaki
Shakeri, Hadis
Pachera, Nathalie
Haliloǧlu, Belma
Özbek, Mehmet Nuri
Ünal, Edip
Yıldırım, Ruken
Godbole, Tushar R.
Yıldız, Melek
Aydın, Banu Küçükemre
Bilheu, Angéline
Suzuki, Ikuo K.

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Citation

Franco, E., Lytrivi, M., Ibrahim, H., Montaser, H., Wakeling, M. N., Fantuzzi, F. ve diğerleri (2020). YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. Journal of Clinical Investigation, 130(12), 6338-6353.

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.

Source

Journal of Clinical Investigation

Volume

130

Issue

12

URI

https://hdl.handle.net/11468/6882

Collections

  • Dahili Tıp Bilimleri Makaleler [356]
  • PubMed İndeksli Yayın Koleksiyonu [168]
  • Scopus İndeksli Yayınlar Koleksiyonu [291]
  • WoS İndeksli Yayınlar Koleksiyonu [332]



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