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Endocrine Abstracts (2019) 66 P24 | DOI: 10.1530/endoabs.66.P24

BSPED2019 Poster Presentations Diabetes 2 (8 abstracts)

Characterizing putative mutant variants of monogenic diabetes

Helena Brezovjakova 1, , Laura Mueller 2 & Francesca Spagnoli 2


1Imperial College School of Medicine, London, UK; 2King’s College London Centre for Stem Cells & Regenerative Medicine, London, UK


Diabetes mellitus is a disease with one of the greatest burdens to both the economy and the individual. Monogenic diabetes mellitus, responsible for neonatal diabetes mellitus and maturity-onset diabetes of the young (MODY), results from one mutation in a single gene. Many of these genes play a role in pancreatic development and their variants can increase risk of type 2 diabetes mellitus (T2DM). Therefore, while the monogenic form of diabetes contributes the least to the overall disease burden, its study can both bring insight into the pathogenesis of polygenic T2DM and advance ß-cell differentiation protocols by improving knowledge of pancreatic development. Previously, novel mutant variants of numerous genes have been identified in a cohort of patients with non-autoimmune puberty-onset diabetes of unknown pathogenesis (strongly suggestive of monogenic diabetes). Two of these genes, an epigenetic modulator (two mutants studied) and a zinc-finger protein (one mutant studied), have been evaluated in silico for the likelihood of causing a deleterious outcome in vivo, yet their exact phenotype remains unknown. Over-expression of human wild-type and mutant variants of these genes was achieved by electroporation of MIN6 murine insulinoma cell line with the respective plasmids. Our findings reveal dysregulation of pancreatic gene expression following mutant transfection. Specifically, both of the studied epigenetic modulator mutants showed down-regulation of Insulin, MafA, and Isl1. This suggests a potential mechanism of ß-cell physiology disruption in the individuals carrying these mutant variants and hence the importance of this epigenetic modulator in endocrine pancreas. Similarly, the zinc-finger mutant showed dysregulation of pancreatic gene expression, particularly it caused reduction in Chga, NeuroD1, and Mafa, all of which are crucial for ß-cell function. This indicates the zinc finger mutant identified in the patient cohort might be a loss-of-function mutation, leading to an impaired mature ß-cell differentiation state. Together, these experiments suggest their role as putative mutant variants leading to monogenic diabetes. Future work will aim to replicate these mutations in human induced pluripotent stem cell line and study them in small rodents to further decipher their phenotype.

Volume 66

47th Meeting of the British Society for Paediatric Endocrinology and Diabetes

Cardiff, UK
27 Nov 2019 - 29 Nov 2019

British Society for Paediatric Endocrinology and Diabetes 

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