Genetic background alters diabetes penetrance in male mice modelling MAFA-MODY

Researchers investigated whether genetic background modifies the effects of Mafa S64F, a variant modelling human MAFA-related maturity-onset diabetes of the young (MODY). They compared male heterozygous mice on a mixed C57BL/6J–SJL/J background with mice backcrossed for eight generations to C57BL/6J. Assessments included glucose regulation, insulin secretion, beta cell ageing signatures, RNA sequencing and mapping of MafA binding to DNA. Glucose tolerance testing across the study used reported sample sizes of n=14–29.

Mixed-background male mice developed overt diabetes, impaired insulin secretion, accelerated beta cell senescence and disrupted circadian gene expression. C57BL/6J-background males maintained glucose regulation and insulin secretion comparable with control littermates. Their islets showed relative normalisation of ageing-related and circadian gene expression, alongside downregulation of retinoic acid signalling and the cell cycle inhibitor p21. Binding analyses implicated retinoic acid receptor-α as a direct MafA target in C57BL/6J islets.

The findings support a role for genetic modifiers in determining the consequences of a pathogenic monogenic diabetes variant. However, these are preclinical findings centred on male mice: they do not establish corresponding modifier effects in patients or demonstrate a treatment strategy for MAFA-MODY.