{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:52:09Z","timestamp":1787025129691,"version":"build-2736575974"},"reference-count":43,"publisher":"American Diabetes Association","issue":"4","license":[{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100007797","name":"Helsingin Yliopisto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007797","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013500","name":"Diabetestutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013500","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Research Council of Finland","doi-asserted-by":"publisher","award":["297466"],"award-info":[{"award-number":["297466"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007083","name":"Orionin Tutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007083","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010135","name":"Finska L\u00e4kares\u00e4llskapet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010135","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010119","name":"Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkl\u00e9ns Minne","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010119","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MetaStem center of excellence","award":["312437"],"award-info":[{"award-number":["312437"]}]},{"DOI":"10.13039\/100010129","name":"Maud Kuistilan Muistos\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010129","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kyllikki and Uolevi Lehikoinen Foundation"},{"DOI":"10.13039\/501100003756","name":"Biomedicum Helsinki-s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003756","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:p>Immediate early response 3 interacting protein 1 (IER3IP1) is an endoplasmic reticulum (ER) resident protein, highly expressed in pancreatic cells and the developing brain cortex. Homozygous mutations in IER3IP1 have been found in individuals with microcephaly and neonatal diabetes, yet the underlying mechanism causing \u03b2-cell failure remains unclear. Here, we used differentiation of genome-edited stem cells into pancreatic islet cells to elucidate the molecular basis of IER3IP1 neonatal diabetes. Using CRISPR\/Cas9 we generated two distinct IER3IP1 mutant human embryonic stem cell lines: a homozygous knock-in model of a patient mutation (IER3IP1V21G), and a knockout (KO) model (IER3IP1\u2212\/\u2212). While these mutant stem cell lines differentiated normally into definitive endoderm and pancreatic progenitors, we observed that IER3IP1-KO stem cell-derived islets (SC-islets) presented a significant decrease in \u03b2-cell numbers and elevated ER stress. Retention using selective hooks assay revealed a threefold reduction in ER-to-Golgi trafficking of proinsulin in IER3IP1 mutant \u03b2-cells. Additionally, IER3IP1 mutant SC-islets implanted into immunocompromised mice displayed defective human insulin secretion, indicating the deleterious impact of IER3IP1 mutations on \u03b2-cell function. Our study provides valuable insights into the role of IER3IP1 in human \u03b2-cell biology and establishes a useful model to investigate ER-to-Golgi trafficking defects within \u03b2-cells.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>IER3IP1 mutations are linked to the development of microcephaly, epilepsy, and early-onset diabetes syndrome 1. However, the underlying molecular mechanisms of cell dysfunction are unknown. Using targeted genome editing, we generated specific IER3IP1 mutations in human embryonic stem cell lines that were differentiated into pancreatic islet lineages. Loss of IER3IP1 resulted in a threefold reduction in endoplasmic reticulum-to-Golgi trafficking of proinsulin in stem cell-derived \u03b2-cells, leading to \u03b2-cell dysfunction both in\u00a0vitro and in\u00a0vivo. Loss of IER3IP1 also triggered increased markers of endoplasmic reticulum stress, indicating the pivotal role of the endoplasmic reticulum-to-Golgi trafficking pathway for \u03b2-cell homeostasis and function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db24-0119","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T14:48:18Z","timestamp":1729694898000},"page":"514-527","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":8,"title":["<i>IER3IP1<\/i>\n                    Mutations Cause Neonatal Diabetes Due to Impaired Proinsulin Trafficking"],"prefix":"10.2337","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0879-1807","authenticated-orcid":false,"given":"Hossam","family":"Montaser","sequence":"first","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Lepp\u00e4nen","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliisa","family":"V\u00e4h\u00e4kangas","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"B\u00e4ck","sequence":"additional","affiliation":[{"name":"2Department of Anatomy, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Grace","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solja","family":"Eurola","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazem","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e4in\u00f6","family":"Lithovius","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1152-2691","authenticated-orcid":false,"given":"Samuel B.","family":"Stephens","sequence":"additional","affiliation":[{"name":"3Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, IA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Barsby","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Balboa","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonna","family":"Saarim\u00e4ki-Vire","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9190-2496","authenticated-orcid":false,"given":"Timo","family":"Otonkoski","sequence":"additional","affiliation":[{"name":"1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland"},{"name":"4Children\u2019s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2024,10,23]]},"reference":[{"key":"2025032018521286700_B1","doi-asserted-by":"crossref","first-page":"101280","DOI":"10.1016\/j.molmet.2021.101280","article-title":"In celebration of a century with insulin \u2013 update of insulin gene mutations in diabetes","volume":"52","author":"St\u00f8y","year":"2021","journal-title":"Mol 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