Recessive TMEM167A variants cause neonatal diabetes, microcephaly, and epilepsy syndrome

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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-09-09
DOI
https://doi.org/10.1172/jci195756
Citations
4
Primary Topic
Pancreatic function and diabetes
Type
article
Field-Weighted Citation Impact
8.03

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article

Recessive TMEM167A variants cause neonatal diabetes, microcephaly, and epilepsy syndrome

Chiara Vinci, Flávia Natividade da Silva, Matthieu Raoux, Raphaël Scharfmann et al.
4 citations
Journal of Clinical Investigation
Pancreatic function and diabetes
8.03
article

Recessive TMEM167A variants cause neonatal diabetes, microcephaly, and epilepsy syndrome

Chiara Vinci, Flávia Natividade da Silva, Matthieu Raoux, Raphaël Scharfmann, Anoop Arunagiri, Theodora Papadopoulou, Sarah Elizabeth Flanagan, James Russ‐Silsby, Fang‐Shin Nian, Maria Lytrivi, Pamela Bowman, S. Hendrickx, Matthew N. Wakeling, A.S. Omar, Thomas W. Laver, Xiaoyan Yi, Georgia Bonfield, Behzat Özkan, Enrico Virgilio, Miriam Cnop, Federica Fantuzzi, Matthew B. Johnson, Anthony Piron, Andrew Tym Hattersley, Sezer Acar, Beyhan Özkaya, Peter Arvan, Bruno J. Santacreu, Sylvia Tielens, Hossam Montaser, Mariana Igoillo‐Esteve, Darshan G. Hegde, Hamed A. Alghamdi, Alexandrine Liboz, Nurgün Kandemir, Iman M. Talaat, Toshiaki Sawatani, Mirza Masoom Abbas, Fauzia Mohsin, Nikhil Shah, Radha Ghildiyal, Elisa De Franco, Jananie Suntharesan, Laurent Nguyen, Molly Govier, Romane Lartigue
article en
4 citations

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.

Journal of Clinical InvestigationVol. 135(22)
Ain Shams University (EG), Centre National de la Recherche Scientifique (FR), Université Libre de Bruxelles (BE), University of Helsinki (FI), Université de Bordeaux (FR), Inserm (FR), University of Liège (BE), Université Paris Cité (FR), University of Exeter (GB), University of Michigan (US), Bangladesh Institute of Research and Rehabilitation for Diabetes Endocrine and Metabolic Disorders (BD), Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College (IN), Erasmus Hospital (BE), Dr. Behçet Uz Çocuk Hastalıkları Hastanesi (TR), Ann Arbor VA Medical Center (US), Northern Area Armed Forces Hospital (SA), Chimie et Biologie des Membranes et des Nanoobjects (FR), Institut Cochin (FR), Walloon Excellence in Lifesciences and Biotechnology (BE), Institut Polytechnique de Bordeaux (FR), Hacettepe University (TR)
University of Pennsylvania, Wellcome Trust, Human Islet Research Network, National Institute for Health and Care Research, Department of Health and Social Care, Université de Bordeaux, ULB Center for Diabetes Research, NIHR Exeter Clinical Research Facility
Openalex Percentile: Top 2%
Pancreatic function and diabetes
8.03
DOIOpen Access PDFOpenAlex
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