1. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
- Author
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Hossam Montaser, Miriam Cnop, Eija Jokitalo, Cristina Cosentino, Mariana Igoillo-Esteve, Piero Marchetti, Banu Kucukemre Aydin, Valérie Senée, Decio L. Eizirik, Pierre Vanderhaeghen, Timo Otonkoski, Céline Demarez, Tushar Godbole, Jonna Saarimäki-Vire, Maria Lytrivi, Väinö Lithovius, Matthew B. Johnson, Ikuo K. Suzuki, Edip Unal, Kashyap A. Patel, Andrew T. Hattersley, Toshiaki Sawatani, Belma Haliloglu, Helena Vihinen, Mehmet Nuri Ozbek, Melek Yildiz, Ruken Yıldırım, Federica Fantuzzi, Matthew Wakeling, Sian Ellard, Hazem Ibrahim, Ying Cai, Cécile Julier, Thomas W Laver, Angéline Bilheu, Nathalie Pachera, Sarah E. Flanagan, Hadis Shakeri, Elisa De Franco, Dicle Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Çocuk Sağlığı ve HastalıklarıAna Bilim Dalı, Ünal, Edip, Yıldırım, Ruken, Centre of Excellence in Stem Cell Metabolism, STEMM - Stem Cells and Metabolism Research Program, Research Programs Unit, Institute of Biotechnology, Electron Microscopy, University Management, Helsinki One Health (HOH), HUS Children and Adolescents, Timo Pyry Juhani Otonkoski / Principal Investigator, and Children's Hospital
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0301 basic medicine ,Male ,Microcephaly ,Embryology ,Newborn disease ,Human Embryonic Stem Cells ,Vesicular Transport Proteins ,Human stem cells ,Research & Experimental Medicine ,medicine.disease_cause ,Endoplasmic Reticulum ,Infant, Newborn, Diseases ,0302 clinical medicine ,Diabetes mellitus ,Pancreas islet beta cell ,3123 Gynaecology and paediatrics ,Insulin-Secreting Cells ,Vesicular transport protein ,Pathology ,Insulin ,TRANSCRIPTION FACTOR ,Precision Medicine ,Induced pluripotent stem cell ,Genetic disorder ,Neurons ,Mutation ,CORTICAL NEUROGENESIS ,Diabetes ,General Medicine ,ER STRESS ,Sciences bio-médicales et agricoles ,Endoplasmic Reticulum Stress ,Cell stress ,Nerve cell ,APOPTOSIS ,3. Good health ,medicine.anatomical_structure ,Medicine, Research & Experimental ,030220 oncology & carcinogenesis ,Endoplasmic reticulum stress ,Female ,Stem cell ,Life Sciences & Biomedicine ,Human ,Research Article ,EXPRESSION ,medicine.medical_specialty ,Neonatal diabetes ,Induced Pluripotent Stem Cells ,Biology ,GOLGI STRESS ,Cell Line ,Cell Biology ,Genetics ,03 medical and health sciences ,PROTEIN RESPONSE CONTRIBUTES ,PUMA ,Internal medicine ,medicine ,Diabetes Mellitus ,Humans ,YIPF5 protein, human ,Science & Technology ,business.industry ,Human embryonic stem cell ,Pancreatic islets ,Endoplasmic reticulum ,Genetic Diseases, Inborn ,Infant, Newborn ,medicine.disease ,Newborn ,Embryonic stem cell ,030104 developmental biology ,Endocrinology ,Metabolism ,Unfolded protein response ,Cancer research ,Commentary ,PANCREATIC BETA-CELLS ,business ,Cell line ,GENERATION - 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., info:eu-repo/semantics/published
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