Year: 2025
Type: article
Abstract: Understanding the genetic causes of diseases that affect pancreatic β cells and neurons can give insights into pathways essential for both cell types. Microcephaly, epilepsy, and diabetes syndrome (MEDS) is a congenital disorder with two known etiological genes, IER3IP1 and YIPF5. Both genes encode proteins involved in endoplasmic reticulum (ER) to Golgi trafficking. We used genome sequencing to identify 6 individuals with MEDS caused by biallelic variants in the potentially novel disease gene TMEM167A. All had neonatal diabetes (diagnosed at <6 months) and severe microcephaly, and 5 also had epilepsy. TMEM167A is highly expressed in developing and adult human pancreas and brain. To gain insights into the mechanisms leading to diabetes, we silenced TMEM167A in EndoC-βH1 cells and knocked-in one patient's variant, p.Val59Glu, in induced pluripotent stem cells (iPSCs). Both TMEM167A depletion in EndoC-βH1 cells and the p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction. The discovery of TMEM167A variants as a genetic cause of MEDS highlights a critical role of TMEM167A in the ER to Golgi pathway in β cells and neurons.
DOI: 10.1172/jci195756
Authors: Enrico Virgilio, Sylvia Tielens, Georgia Bonfield, Fang-Shin Nian, Toshiaki Sawatani, Chiara Vinci, Molly Govier, Hossam Montaser, Romane Lartigue, Anoop Arunagiri, Alexandrine Liboz, Flavia Natividade Da Silva, Maria Lytrivi, Theodora Papadopoulou, Matthew N. Wakeling, James Russ-Silsby, Pamela Bowman, Matthew B. Johnson, Thomas W. Laver, Anthony Piron, Xiaoyan Yi, Federica Fantuzzi, Sirine Hendrickx, Mariana Igoillo-Esteve, Bruno J. Santacreu, Jananie Suntharesan, Radha Ghildiyal, Darshan Hegde, Nikhil Shah, Sezer Acar, Beyhan Özkaya Dönmez, Behzat Özkan, Fauzia Mohsin, Iman M. Talaat, Mohamed Tarek Abbas, Omar Tarek Abbas, Hamed Ali Alghamdi, Nurgun Kandemir, Sarah E. Flanagan, Raphael Scharfmann, Peter Arvan, Matthieu Raoux, Laurent Nguyen, Andrew T. Hattersley, Miriam Cnop, Elisa De Franco
Institutions: Université Libre de Bruxelles, University of Liège, University of Exeter, University of Helsinki, Centre National de la Recherche Scientifique, Université de Bordeaux, Chimie et Biologie des Membranes et des Nanoobjects, Institut Polytechnique de Bordeaux, University of Michigan, Michigan Medicine, Erasmus Hospital, Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College, Dr. Behçet Uz Çocuk Hastalıkları Hastanesi, Bangladesh Institute of Research and Rehabilitation for Diabetes Endocrine and Metabolic Disorders, Ain Shams University, Northern Area Armed Forces Hospital, Hacettepe University, Inserm, Université Paris Cité, Institut Cochin
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: University of Pennsylvania, Wellcome Trust, Human Islet Research Network, National Institute for Health and Care Research, Department of Health and Social Care, Diabetes UK, European Foundation for the Study of Diabetes, Fonds De La Recherche Scientifique - FNRS, Université de Bordeaux, Société Francophone du Diabète, Novo Nordisk Fonden, ULB Center for Diabetes Research, NIHR Exeter Clinical Research Facility
Awards: G1419702618, Unlocking the translational potential of extreme forms of autoimmune diabetes by uncovering heterogeneous mechanisms of beta-cell autoimmunity, G4257221958, Non-coding mutations in congenital hyperinsulinism: deciphering the role of gene dysregulation in human disease, G4849004728, G5749247687, G6864439215, G7212170208, Human-specific gene regulation in pancreatic beta-cell development
OpenAlex ID: W4414081985