RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Regulatory factor X 6 (RFX6) is indispensable for pancreatic endocrine development and differentiation. The RFX6 protein-truncating variant p.His293LeufsTer7 is significantly enriched in the Finnish population with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 diabetes (T2D) and gestational diabetes. To understand the role of this variant in β-cell development and function, we generated allelic series of isogenic pluripotent stem cell models and directed them into pancreatic islet lineages (SC-islets). Expectedly, in-vitro models of the homozygous RFX6 −/− variant failed to generate pancreatic endocrine cells, recapitulating the phenotype in Mitchell-Riley syndrome. Notably, heterozygous RFX6 +/− derived SC-islets showed reduced β-cell maturation markers and calcium oscillations, resulting in defective insulin secretion, without affecting β-cell number or insulin content. The reduced insulin secretion is sustained during in-vivo implantation studies, consistent with the susceptibility of the carriers to develop diabetes. Teaser Modeling RFX6 -assocciated neonatal and type-2 diabetes using allelic series stem cell-derived islets in-vitro and in-vivo .