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YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.

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.

SUBMITTER: De Franco E

PROVIDER: S-EPMC7685733 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.

De Franco Elisa E Lytrivi Maria M Ibrahim Hazem H Montaser Hossam H Wakeling Matthew N MN Fantuzzi Federica F Patel Kashyap K Demarez Céline C Cai Ying Y Igoillo-Esteve Mariana M Cosentino Cristina C Lithovius Väinö V Vihinen Helena H Jokitalo Eija E Laver Thomas W TW Johnson Matthew B MB Sawatani Toshiaki T Shakeri Hadis H Pachera Nathalie N Haliloglu Belma B Ozbek Mehmet Nuri MN Unal Edip E Yıldırım Ruken R Godbole Tushar T Yildiz Melek M Aydin Banu B Bilheu Angeline A Suzuki Ikuo I Flanagan Sarah E SE Vanderhaeghen Pierre P Senée Valérie V Julier Cécile C Marchetti Piero P Eizirik Decio L DL Ellard Sian S Saarimäki-Vire Jonna J Otonkoski Timo T Cnop Miriam M Hattersley Andrew T AT

The Journal of clinical investigation 20201201 12

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 expr ...[more]

PMID: 33164986

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Project description:BackgroundMetabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells.MethodsA retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage.ResultsWe found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression.ConclusionsOur data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.

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YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.

Publications

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.

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