Pellegrini_2021_J.Clin.Endocrinol.Metab__

CONTEXT: MODY8 is a rare form of monogenic diabetes characterized by a mutation in CEL (carboxyl-ester-lipase) gene, which leads to exocrine pancreas dysfunction, followed by beta cell failure. Induced pluripotent stem cells can differentiate into functional beta cells. Thus, beta cells from MODY8 patients can be generated in vitro and used for disease modelling and cell replacement therapy. DESIGN AND RESULTS: A genetic study was performed in a patient suspected of monogenic diabetes. A novel heterozygous pathogenic variant in CEL (c.1818delC) was identified in the Proband, allowing diagnosis of MODY8. Three MODY8-iPSC clones were reprogrammed from skin fibroblasts of the patient, and their pluripotency and genomic stability confirmed. All three MODY8-iPSC differentiated into beta cells following developmental stages. MODY8-iPSC-derived beta cells were able to secrete insulin upon glucose dynamic perifusion. CEL gene was not expressed in iPSC nor during any steps of endocrine differentiation. CONCLUSIONS: iPSC lines from a MODY8 patient with a novel pathogenic variant in the CEL gene were generated, they are capable of differentiation into endocrine cell and beta cell function is preserved in mutated cells. These results set the basis for in vitro modelling of the disease and potentially for autologous beta cell replacement.