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YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

The Journal of clinical investigation, 2020-12, Vol.130 (12), p.6338-6353 [Peer Reviewed Journal]

COPYRIGHT 2020 American Society for Clinical Investigation ;2020 De Franco et al. 2020 De Franco et al. ;ISSN: 0021-9738 ;EISSN: 1558-8238 ;DOI: 10.1172/jci141455 ;PMID: 33164986

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Title:
YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
Author: De Franco, Elisa ; Lytrivi, Maria ; Ibrahim, Hazem ; Montaser, Hossam ; Wakeling, Matthew N ; Fantuzzi, Federica ; Patel, Kashyap ; Demarez, Céline ; Cai, Ying ; Igoillo-Esteve, Mariana ; Cosentino, Cristina ; Lithovius, Väinö ; Vihinen, Helena ; Jokitalo, Eija ; Laver, Thomas W ; Johnson, Matthew B ; Sawatani, Toshiaki ; Shakeri, Hadis ; Pachera, Nathalie ; Haliloglu, Belma ; Ozbek, Mehmet Nuri ; Unal, Edip ; Yıldırım, Ruken ; Godbole, Tushar ; Yildiz, Melek ; Aydin, Banu ; Bilheu, Angeline ; Suzuki, Ikuo ; Flanagan, Sarah E ; Vanderhaeghen, Pierre ; Senée, Valérie ; Julier, Cécile ; Marchetti, Piero ; Eizirik, Decio L ; Ellard, Sian ; Saarimäki-Vire, Jonna ; Otonkoski, Timo ; Cnop, Miriam ; Hattersley, Andrew T
Subjects: Causes of ; Cell Line ; Development and progression ; Diabetes ; Diabetes Mellitus - embryology ; Diabetes Mellitus - genetics ; Diabetes Mellitus - pathology ; Diseases ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress - genetics ; Female ; Genetic aspects ; Genetic Diseases, Inborn - embryology ; Genetic Diseases, Inborn - genetics ; Genetic Diseases, Inborn - pathology ; Health aspects ; Human Embryonic Stem Cells - metabolism ; Human Embryonic Stem Cells - pathology ; Humans ; Induced Pluripotent Stem Cells - metabolism ; Induced Pluripotent Stem Cells - pathology ; Infant, Newborn ; Infant, Newborn, Diseases - embryology ; Infant, Newborn, Diseases - genetics ; Infant, Newborn, Diseases - pathology ; Infants (Newborn) ; Insulin-Secreting Cells - metabolism ; Insulin-Secreting Cells - pathology ; Male ; Microcephaly ; Microcephaly - embryology ; Microcephaly - genetics ; Microcephaly - pathology ; Mutation ; Neurons - metabolism ; Neurons - pathology ; Pediatric research ; Physiological aspects ; Stress (Physiology) ; Vesicular Transport Proteins - genetics ; Vesicular Transport Proteins - metabolism
Is Part Of: The Journal of clinical investigation, 2020-12, Vol.130 (12), p.6338-6353
Description: 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.
Publisher: United States: American Society for Clinical Investigation
Language: English
Identifier: ISSN: 0021-9738
EISSN: 1558-8238
DOI: 10.1172/jci141455
PMID: 33164986
Source: Geneva Foundation Free Medical Journals
Open Access: PubMed Central
AUTh Library subscriptions: ProQuest Central
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YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

COPYRIGHT 2020 American Society for Clinical Investigation ;2020 De Franco et al. 2020 De Franco et al. ;ISSN: 0021-9738 ;EISSN: 1558-8238 ;DOI: 10.1172/jci141455 ;PMID: 33164986

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