RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function

Area of Science:

• Endocrinology
• Developmental Biology
• Genetics

Background:

• Regulatory factor X 6 (RFX6) is essential for pancreatic endocrine development.
• A specific RFX6 variant is common in Finland, linked to increased type 2 and gestational diabetes risk.
• The mechanism behind this predisposition is not well understood.

Purpose of the Study:

• To investigate the role of the RFX6 variant in beta cell development and function.
• To create and utilize isogenic stem cell models for studying RFX6's impact.
• To elucidate the cellular and molecular mechanisms underlying diabetes predisposition.

Main Methods:

• Generated isogenic human embryonic and patient-derived stem cell models using CRISPR.
• Differentiated stem cells into stem-cell-derived islets (SC-islets).
• Implanted SC-islets into immunocompromised mice for in vivo assessment.

Main Results:

• Homozygous RFX6 knockout models failed to produce insulin-secreting beta cells.
• Heterozygous RFX6 models showed haploinsufficiency, reduced beta cell maturation, and impaired insulin secretion.
• Reduced insulin secretion in heterozygous models persisted after in vivo implantation.

Conclusions:

• RFX6 is critical for maintaining the pancreatic progenitor pool and beta cell function.
• RFX6 haploinsufficiency impairs insulin secretion without affecting beta cell mass or insulin content.
• This study provides a model for understanding diabetes etiology in carriers of RFX6 loss-of-function variants.