Journal Article

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

Dönmez, Beyhan Özkaya, Russ-Silsby, James, Kandemir, Nurgun, Fantuzzi, Federica, Yi, Xiaoyan, Alghamdi, Hamed Ali, Arvan, Peter, Lytrivi, Maria, Piron, Anthony, De Franco, Elisa, Özkan, Behzat, Mohsin, Fauzia, Abbas, Mohamed Tarek, Tielens, Sylvia, Govier, Molly, Flanagan, Sarah E., Igoillo-Esteve, Mariana, Raoux, Matthieu, Nian, Fang-Shin, Papadopoulou, Theodora, Johnson, Matthew B., Laver, Thomas W., Hegde, Darshan, Cnop, Miriam, Sawatani, Toshiaki, Montaser, Hossam, Hendrickx, Sirine, Shah, Nikhil, Lartigue, Romane, Wakeling, Matthew N., Santacreu, Bruno J., Liboz, Alexandrine, Talaat, Iman M., Hattersley, Andrew T., Scharfmann, Raphael, Da Silva, Flavia Natividade, Abbas, Omar Tarek, Virgilio, Enrico, Bonfield, Georgia, Bowman, Pamela, Acar, Sezer, Suntharesan, Jananie, Ghildiyal, Radha, Nguyen, Laurent, Vinci, Chiara, Arunagiri, Anoop

2025

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adults / Amino Acid Substitution / B cells / Beta cells / Brain / Cell biology / Diabetes / Diabetes Mellitus / Diabetes Mellitus - genetics / Diabetes Mellitus - metabolism / Diabetes Mellitus - pathology / Disease / DNA sequencing / Endocrinology / Endoplasmic Reticulum / Endoplasmic Reticulum - genetics / Endoplasmic Reticulum - metabolism / Epilepsy / Epilepsy - genetics / Epilepsy - metabolism / Epilepsy - pathology / Epileptic Syndromes / Epileptic Syndromes - genetics / Epileptic Syndromes - metabolism / Epileptic Syndromes - pathology / Female / Genes / Genetic aspects / Genetic diseases / Genetics / Genomes / Genomics / Golgi Apparatus / Golgi Apparatus - genetics / Golgi Apparatus - metabolism / Golgi cells / Human health sciences / Humans / Induced Pluripotent Stem Cells / Induced Pluripotent Stem Cells - metabolism / Induced Pluripotent Stem Cells - pathology / Infant / Infant, Newborn / Infant, Newborn, Diseases / Infant, Newborn, Diseases - genetics / Infant, Newborn, Diseases - metabolism / Infants (Newborn) / Inhibitory postsynaptic potentials / Insulin / Insulin-Secreting Cells / Insulin-Secreting Cells - metabolism / Insulin-Secreting Cells - pathology / Life Sciences / Male / Medicine (all) / Membrane Proteins / Membrane Proteins - genetics / Membrane Proteins - metabolism / Microcephaly / Microcephaly - genetics / Microcephaly - metabolism / Microcephaly - pathology / Microencephaly / Mutation, Missense / Neonates / Neurodevelopment / Neurologie / Neurology / Neurons / Nucleotide sequencing / Pancreas / Pluripotency / Proteins / Sciences de la santé humaine / Stem cells