Recessive TMEM167A variants cause neonatal diabetes, microcephaly and epilepsy syndrome

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Abstract

Understanding the genetic causes of diseases affecting 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 aetiological 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 novel disease gene, TMEM167A. All had neonatal diabetes (diagnosed <6 months) and severe microcephaly, five 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 new genetic cause of MEDS highlights a critical role of TMEM167A in the ER to Golgi pathway in β cells and neurons.

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 G. Hegde, Nikhil Avnish Shah, Sezer Acar, Beyhan Özkaya Dönmez, Behzat Özkan, Fauzia Mohsin, Iman M. Talaat, Mohamed Tarek Abbas, Omar Saied 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