BES2022 BES 2022 Abstracts (23 abstracts)
Understanding pathogenic mechanisms and identifying therapeutic avenues in MEHMO syndrome using patient’s induced pluripotent stem cells
Shakeri Hadis 1 , Akcay Izzet Mehmet 1 , Bansal Mayank 1 , Cai Ying 1 , Vinci Chiara 1 , Pachera Nathalie 1 , Willems Hanne 1 , Fantuzzi Federica 1 , Tong Yue 1 , Gasperikova Daniela 2 & Cnop Miriam 1,3
1ULB center for diabetes research, Universite Libre de Bruxelles, Brussels, Belgium; 2Department of Metabolic Disease Research, Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia; 3Division of Endocrinology, Erasmus Hospital, Universite Libre de Bruxelles, Brussels, Belgium
Background and aims: MEHMO is an X-linked syndrome comprising Mental retardation, Epilepsy, Hypogenitalism, Microcephaly and Obesity. It is caused by a damaging p.Ile465Serfs frameshift mutation in EIF2S3 that encodes the □ subunit of eukaryotic translation initiation factor 2 (eIF2), essential for protein synthesis and regulation of the integrated stress response. Patients with this EIF2S3 mutation also have neonatal hypoglycemia, early onset insulin- dependent diabetes and hypopituitarism. Here we investigated pathogenic mechanisms and potential treatments using patient’s induced pluripotent stem cell (iPSC)-derived pancreatic β- cells.
Materials and methods: Blood cells from a MEHMO patient with the p.Ile465Serfs mutation who developed diabetes at age 10 months were reprogrammed into iPSCs using the Yamanaka factors. iPSCs were differentiated in vitro into β-cells and exposed to endoplasmic reticulum (ER) stressors thapsigargin (1 μM) and brefeldin A (0.02 μg/ml). We investigated whether protection was conferred by exenatide (GLP-1 receptor agonist, 50 nM), forskolin (cAMP inducer, 10 μM) and ISRIB (integrated stress response inhibitor, 200 nM).
Results: Patient iPSCs showed morphological and developmental defects compared to control cells. Expression of crucial β-cell developmental markers NKX6.1 and PDX-1 was reduced during differentiation. The β-cell yield at the end of differentiation was lower compared to control cells (37·3% vs 62·2%, P<0.0001), as was insulin content (11·2 vs 19·8 ng insulin/μg protein, P<0.05, n=8). Basal β-cell death was not different (7·3% vs 8·4%, n=8-13), but the EIF2S3 mutation sensitized the cells to thapsigargin (24·7% apoptosis vs 16·4%, P<0.05) and brefeldin (36·7% vs 26·6%, P<0.001). ISRIB improved cell morphology and NKX6.1 and PDX-1 expression along the differentiation but did not ameliorate β-cell survival. Exenatide and forskolin conferred protection against thapsigargin and brefeldin.
Conclusions: The diabetogenic EIF2S3 frameshift mutation alters patient’s iPSC-derived β-cell development and exacerbates ER stress-induced apoptosis. ISRIB rescues the developmental defect, and GLP-1 analogs protect from ER stress. This study points to an important role of EIF2S3 in β-cells and identifies novel therapeutic avenues for MEHMO syndrome. The patient iPSCs provide a powerful disease-in-a-dish model and can be used to study other clinical characteristics of MEHMO syndrome.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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