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Endocrine Abstracts (2020) 71 003 | DOI: 10.1530/endoabs.71.003

1ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium; 2Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium 3Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; 4Stem cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 5Endocrinology and Metabolism, Department of Medicine and Surgery, University of Parma, Parma, Italy; 6Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki, Helsinki, Finland 7Yeditepe University Hospital, Istanbul, Turkey; 8Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey; 9Dicle University, Faculty of Medicine, Department of Pediatric Endocrinology, Diyarbakir, Turkey 10Harmony Health Hub, Nashik, India; 11Istanbul University, Istanbul Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey; 12Kanuni Sultan Suleyman Training and Research Hospital, Department of Pediatric Endocrinology, Istanbul, Turkey; 13Institute of Interdisciplinary Research (IRIBHM), ULB Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium; 14VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; 15Department of Neurosciences, Leuven Brain Institute, KULeuven, Leuven, Belgium; 16Welbio, Université Libre de Bruxelles, Brussels, Belgium; 17Université de Paris, Faculté de Médecine Paris-Diderot, U958, Paris, France; 18Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 19Indiana Biosciences Research Institute, Indianapolis, IN, USA; 20Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
*Contributed equally

Objective: Neonatal diabetes is caused by single gene mutations reducing pancreatic β-cell number or impairing β-cell function. Understanding the genetic underpinnings of rare diabetes subtypes highlights fundamental biological processes in β-cells. Our aim was to explore the genetic basis of a syndrome characterized by neonatal diabetes, microcephaly and epilepsy.

Methods: We performed whole genome sequencing for 2 unrelated patients with neonatal diabetes (diagnosed aged 5 and 9 weeks), born to consanguineous parents. Replication studies were performed in 187 patients with early-onset diabetes by a targeted next generation sequencing assay. 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.

Results: 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. 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.

Conclusions: We report recessive YIPF5 mutations as the genetic cause of a novel syndrome of microcephaly, epilepsy and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β-cells and neurons. This is the first report of mutations disrupting the ER-to-Golgi trafficking resulting in diabetes.

Volume 71

Belgian Endocrine Society 2020

Online, Online
11 Nov 2020 - 11 Nov 2020

Belgian Endocrine Society 

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