YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
dc.contributor.author | De Franco, E | |
dc.contributor.author | Lytrivi, M | |
dc.contributor.author | Ibrahim, H | |
dc.contributor.author | Montaser, H | |
dc.contributor.author | Wakeling, M | |
dc.contributor.author | Fantuzzi, F | |
dc.contributor.author | Patel, K | |
dc.contributor.author | Demarez, C | |
dc.contributor.author | Cai, Y | |
dc.contributor.author | Igoillo-Esteve, M | |
dc.contributor.author | Cosentino, C | |
dc.contributor.author | Lithovius, V | |
dc.contributor.author | Vihinen, H | |
dc.contributor.author | Jokitalo, E | |
dc.contributor.author | Laver, TW | |
dc.contributor.author | Johnson, MB | |
dc.contributor.author | Sawatani, T | |
dc.contributor.author | Shakeri, H | |
dc.contributor.author | Pachera, N | |
dc.contributor.author | Haliloglu, B | |
dc.contributor.author | Ozbek, MN | |
dc.contributor.author | Unal, E | |
dc.contributor.author | Yıldırım, R | |
dc.contributor.author | Godbole, T | |
dc.contributor.author | Yildiz, M | |
dc.contributor.author | Aydin, B | |
dc.contributor.author | Bilheu, A | |
dc.contributor.author | Suzuki, I | |
dc.contributor.author | Flanagan, SE | |
dc.contributor.author | Vanderhaeghen, P | |
dc.contributor.author | Senée, V | |
dc.contributor.author | Julier, C | |
dc.contributor.author | Marchetti, P | |
dc.contributor.author | Eizirik, DL | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Saarimäki-Vire, J | |
dc.contributor.author | Otonkoski, T | |
dc.contributor.author | Cnop, M | |
dc.contributor.author | Hattersley, AT | |
dc.date.accessioned | 2020-09-02T12:19:02Z | |
dc.date.issued | 2020-11-09 | |
dc.description.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 endoplasmic reticulum (ER)-to-Golgi trafficking. 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 three human β-cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knock-out and mutation knock-in 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-cellsensitivity 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-to65 Golgi trafficking resulting in diabetes. | en_GB |
dc.description.sponsorship | Diabetes UK | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.description.sponsorship | Royal Society | en_GB |
dc.identifier.citation | Published online 9 November 2020 | en_GB |
dc.identifier.doi | 10.1172/JCI141455 | |
dc.identifier.grantnumber | 19/0005971 | en_GB |
dc.identifier.grantnumber | WT098395/Z/12/Z | en_GB |
dc.identifier.grantnumber | 105636/Z/14/Z | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/122680 | |
dc.language.iso | en | en_GB |
dc.publisher | American Society for Clinical Investigation | en_GB |
dc.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. | |
dc.subject | Diabetes | en_GB |
dc.subject | Microcephaly | en_GB |
dc.subject | Epilepsy | en_GB |
dc.subject | Epilepsy | en_GB |
dc.subject | Endoplasmic reticulum | en_GB |
dc.subject | Golgi | en_GB |
dc.subject | Mutation | en_GB |
dc.title | YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2020-09-02T12:19:02Z | |
dc.identifier.issn | 0021-9738 | |
dc.description | This is the final version. Available on open access from the American Society for Clinical Investigation via the DOI in this record | en_GB |
dc.identifier.journal | Journal of Clinical Investigation | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2020-08-27 | |
exeter.funder | ::Diabetes UK | en_GB |
exeter.funder | ::Wellcome Trust | en_GB |
exeter.funder | ::Wellcome Trust | en_GB |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2020-08-27 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2020-09-01T15:16:58Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2020-11-20T15:52:50Z | |
refterms.panel | A | en_GB |
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Except where otherwise noted, this item's licence is described as © 2020, De Franco et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.