RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Ibrahim, H.; Balboa, D.; Saarimäki-Vire, J.; Montaser, H.; Dyachok, O.; Lund, P.-E.; Omar-Hmeadi, M.; Kvist, J.; Dwivedi, O. P.; Lithovius, V.; Barsby, T.; Chandra, V.; Eurola, S.; Ustinov, J.; Tuomi, T.; Miettinen, P. J.; Barg, S.; Tengholm, A.; Otonkoski, T.

doi:10.1101/2023.11.15.567202

bioRxiv · 10.1101/2023.11.15.567202

RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Ibrahim, H.·Balboa, D.·Saarimäki-Vire, J.·Montaser, H.·Dyachok, O.·Lund, P.-E.·Omar-Hmeadi, M.·Kvist, J.·Dwivedi, O. P.·Lithovius, V.·Barsby, T.·Chandra, V.·Eurola, S.·Ustinov, J.·Tuomi, T.·Miettinen, P. J.·Barg, S.·Tengholm, A.·Otonkoski, T.

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Abstract

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 {beta}-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 {beta}-cell maturation markers and calcium oscillations, resulting in defective insulin secretion, without affecting {beta}-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. TeaserModeling RFX6-assocciated neonatal and type-2 diabetes using allelic series stem cell-derived islets in-vitro and in-vivo.

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Ibrahim, H., Balboa, D., Saarimäki-Vire, J., Montaser, H., Dyachok, O., Lund, P.-E., Omar-Hmeadi, M., Kvist, J., Dwivedi, O. P., Lithovius, V., Barsby, T., Chandra, V., Eurola, S., Ustinov, J., Tuomi, T., Miettinen, P. J., Barg, S., Tengholm, A., Otonkoski, T.. 2023-11-16. RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell functionality. https://doi.org/10.1101/2023.11.15.567202

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