Silvia Pellegrini, Giovanni B Pipitone, Alessandro Cospito, Fabio Manenti, Gaia Poggi, Marta T Lombardo, Rita Nano, Gianvito Martino, Maurizio Ferrari, Paola Carrera, Valeria Sordi, Lorenzo Piemonti
The Journal of Clinical Endocrinology & Metabolism, Volume 106, Issue 5, May 2021, Pages e2322–e2333
https://doi.org/10.1210/clinem/dgaa986
Maturity-onset diabetes of the young (MODY) 8 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 β-cell failure. Induced pluripotent stem cells can differentiate into functional β cells. Thus, β cells from MODY8 patients can be generated in vitro and used for disease modelling and cell replacement therapy.
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 (induced pluripotent stem cell) clones were reprogrammed from skin fibroblasts of the patient, and their pluripotency and genomic stability confirmed. All 3 MODY8-iPSC differentiated into β cells following developmental stages. MODY8-iPSC–derived β cells were able to secrete insulin upon glucose dynamic perifusion. The CEL gene was not expressed in iPSCs nor during any steps of endocrine differentiation.
iPSC lines from a MODY8 patient with a novel pathogenic variant in the CEL gene were generated; they are capable of differentiation into endocrine cells, and β-cell function is preserved in mutated cells. These results set the basis for in vitro modelling of the disease and potentially for autologous β-cell replacement.
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