[en] 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.
Disciplines :
Neurology
Author, co-author :
Virgilio, Enrico; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Tielens, Sylvia ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Bonfield, Georgia; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Nian, Fang-Shin ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Sawatani, Toshiaki; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Vinci, Chiara; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Govier, Molly; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Montaser, Hossam; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Lartigue, Romane; University of Bordeaux, CNRS, Bordeaux INP, Chemistry & Biology of Membranes & Nano-objects, UMR 5248, Pessac, France
Arunagiri, Anoop ; Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, USA
Liboz, Alexandrine; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Da Silva, Flavia Natividade; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Lytrivi, Maria ; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium ; Division of Endocrinology, ULB Erasmus Hospital, Brussels University Hospital, Université Libre de Bruxelles, Brussels, Belgium
Papadopoulou, Theodora; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Wakeling, Matthew N; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Russ-Silsby, James; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Bowman, Pamela; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Johnson, Matthew B ; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Laver, Thomas W ; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Piron, Anthony; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Yi, Xiaoyan; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Fantuzzi, Federica; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Hendrickx, Sirine; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Igoillo-Esteve, Mariana ; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Santacreu, Bruno J; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
Suntharesan, Jananie; Sirimavo Bandaranayake Specialized Children's Hospital, Peradeniya, Sri Lanka
Ghildiyal, Radha; Department of Pediatrics, Lokmanya Tilak Municipal Medical College and Lokmanya Tilak Municipal General Hospital, Mumbai, India
Hegde, Darshan; Department of Pediatrics, Lokmanya Tilak Municipal Medical College and Lokmanya Tilak Municipal General Hospital, Mumbai, India
Shah, Nikhil; Department of Pediatrics, Lokmanya Tilak Municipal Medical College and Lokmanya Tilak Municipal General Hospital, Mumbai, India
Acar, Sezer; Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
Dönmez, Beyhan Özkaya; Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
Özkan, Behzat; Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
Mohsin, Fauzia; Department of Paediatrics, BIRDEM General Hospital, Dhaka, Bangladesh
Talaat, Iman M; Pediatric Department and
Abbas, Mohamed Tarek; Internal medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Abbas, Omar Tarek; Internal medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Alghamdi, Hamed Ali; Northern Area Armed Forces Hospital, King Khalid Military City, Saudi Arabia
Kandemir, Nurgun; Hacettepe University, Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
Flanagan, Sarah E ; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Scharfmann, Raphael ; Université Paris Cité, Institut Cochin, INSERM, Paris, France
Arvan, Peter ; Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan, USA
Raoux, Matthieu; University of Bordeaux, CNRS, Bordeaux INP, Chemistry & Biology of Membranes & Nano-objects, UMR 5248, Pessac, France
Nguyen, Laurent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; WEL Research Institute, Wavre, Belgium
Hattersley, Andrew T ; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Cnop, Miriam; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium ; Division of Endocrinology, ULB Erasmus Hospital, Brussels University Hospital, Université Libre de Bruxelles, Brussels, Belgium ; WEL Research Institute, Wavre, Belgium
De Franco, Elisa; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
Wellcome Trust EFSD - European Foundation for the Study of Diabetes NNF - Novo Nordisk Fonden FWO - Research Foundation Flanders Walloon region F.R.S.-FNRS - Fonds de la Recherche Scientifique EU - European Union SFD - Société Francophone du Diabète
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