YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

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dc.authorid0000-0002-9809-0977en_US
dc.contributor.authorde Franco, Elisa
dc.contributor.authorLytrivi, Maria
dc.contributor.authorIbrahim, Hazem
dc.contributor.authorMontaser, Hossam
dc.contributor.authorWakeling, Matthew Neil
dc.contributor.authorFantuzzi, Federica
dc.contributor.authorPatel, Kashyap A.
dc.contributor.authorDemarez, Céline
dc.contributor.authorCai, Ying
dc.contributor.authorIgoillo-Esteve, Mariana
dc.contributor.authorCosentino, Cristina
dc.contributor.authorLithovius, Väinö
dc.contributor.authorVihinen, Helena
dc.contributor.authorJokitalo, Eija
dc.contributor.authorLaver, Thomas William
dc.contributor.authorJohnson, Matthew B.
dc.contributor.authorSawatani, Toshiaki
dc.contributor.authorShakeri, Hadis
dc.contributor.authorPachera, Nathalie
dc.contributor.authorHaliloǧlu, Belma
dc.contributor.authorÖzbek, Mehmet Nuri
dc.contributor.authorÜnal, Edip
dc.contributor.authorYıldırım, Ruken
dc.contributor.authorGodbole, Tushar R.
dc.contributor.authorYıldız, Melek
dc.contributor.authorAydın, Banu Küçükemre
dc.contributor.authorBilheu, Angéline
dc.contributor.authorSuzuki, Ikuo K.
dc.date.accessioned2021-05-07T13:01:59Z
dc.date.available2021-05-07T13:01:59Z
dc.date.issued2020en_US
dc.departmentDicle Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Çocuk Sağlığı ve HastalıklarıAna Bilim Dalıen_US
dc.descriptionWOS:000600340600004
dc.descriptionPMID: 33164986
dc.description.abstractNeonatal 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.en_US
dc.identifier.citationFranco, 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.en_US
dc.identifier.doi10.1172/JCI141455
dc.identifier.endpage6353en_US
dc.identifier.issue12en_US
dc.identifier.pmid33164986
dc.identifier.scopus2-s2.0-85097112734
dc.identifier.scopusqualityQ1
dc.identifier.startpage6338en_US
dc.identifier.urihttps://hdl.handle.net/11468/6882
dc.identifier.volume130en_US
dc.identifier.wosWOS:000600340600004
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorÜnal, Edip
dc.institutionauthorYıldırım, Ruken
dc.language.isoenen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.ispartofJournal of Clinical Investigation
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectVesicular transport proteinen_US
dc.subjectYIPF5 protein, humanen_US
dc.subjectCell lineen_US
dc.subjectDiabetes mellitusen_US
dc.subjectEmbryologyen_US
dc.subjectEndoplasmic reticulum stressen_US
dc.subjectFemaleen_US
dc.subjectGenetic disorderen_US
dc.subjectGeneticsen_US
dc.subjectHuman embryonic stem cellen_US
dc.subjectHumanen_US
dc.subjectInduced pluripotent stem cellen_US
dc.subjectMaleen_US
dc.subjectMetabolismen_US
dc.subjectMicrocephalyen_US
dc.subjectMutationen_US
dc.subjectNerve cellen_US
dc.subjectNewbornen_US
dc.subjectNewborn diseaseen_US
dc.subjectPancreas islet beta cellen_US
dc.subjectPathologyen_US
dc.titleYIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stressen_US
dc.titleYIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
dc.typeArticleen_US

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