YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress PMID: 33164986

Target-related Cytokines

2026-09-23

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

J Clin Invest. 2020 Dec 1;130(12):6338-6353. doi: 10.1172/JCI141455.

Elisa De Franco ¹ , Maria Lytrivi ² ³ , Hazem Ibrahim ⁴ , Hossam Montaser ⁴ , Matthew N Wakeling ¹ , Federica Fantuzzi ² ⁵ , Kashyap Patel ¹ , Céline Demarez ² , Ying Cai ² , Mariana Igoillo-Esteve ² , Cristina Cosentino ² , Väinö Lithovius ⁴ , Helena Vihinen ⁶ , Eija Jokitalo ⁶ , Thomas W Laver ¹ , Matthew B Johnson ¹ , Toshiaki Sawatani ² , Hadis Shakeri ² , Nathalie Pachera ² , Belma Haliloglu ⁷ , Mehmet Nuri Ozbek ⁸ , Edip Unal ⁹ , Ruken Yıldırım ⁹ , Tushar Godbole ¹⁰ , Melek Yildiz ¹¹ , Banu Aydin ¹² , Angeline Bilheu ¹³ , Ikuo Suzuki ¹³ ¹⁴ ¹⁵ , Sarah E Flanagan ¹ , Pierre Vanderhaeghen ¹³ ¹⁴ ¹⁵ ¹⁶ , Valérie Senée ¹⁷ , Cécile Julier ¹⁷ , Piero Marchetti ¹⁸ , Decio L Eizirik ² ¹⁶ ¹⁹ , Sian Ellard ¹ , Jonna Saarimäki-Vire ⁴ , Timo Otonkoski ⁴ ²⁰ , Miriam Cnop ² ³ , Andrew T Hattersley ¹

Affiliations

1. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom.
2. ULB Center for Diabetes Research and.
3. Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
4. Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
5. Endocrinology and Metabolism, Department of Medicine and Surgery, University of Parma, Parma, Italy.
6. Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
7. Yeditepe University Hospital, Istanbul, Turkey.
8. Gazi Yaşargil Education and Research Hospital, Diyarbakır, Turkey.
9. Dicle University, Faculty of Medicine, Department of Pediatric Endocrinology, Diyarbakır, Turkey.
10. Harmony Health Hub, Nashik, India.
11. Istanbul University, Istanbul Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey.
12. Kanuni Sultan Suleyman Training and Research Hospital, Department of Pediatric Endocrinology, Istanbul, Turkey.
13. Institute of Interdisciplinary Research (IRIBHM), ULB Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium.
14. VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
15. Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
16. Welbio, Université Libre de Bruxelles, Brussels, Belgium.
17. Université de Paris, Faculté de Médecine Paris-Diderot, U958, Paris, France.
18. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
19. Indiana Biosciences Research Institute, Indianapolis, Indiana, USA.
20. Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Abstract

Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and Epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress-induced Apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, Epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.

Keywords

Cell Biology; Cell stress; Diabetes; Genetics; Human stem cells.