RFX6 regulates insulin secretion by modulating Ca2+ homeostasis in human β cells

Cell Rep. 2014 Dec 24;9(6):2206-18. doi: 10.1016/j.celrep.2014.11.010. Epub 2014 Dec 11.


Development and function of pancreatic β cells involve the regulated activity of specific transcription factors. RFX6 is a transcription factor essential for mouse β cell differentiation that is mutated in monogenic forms of neonatal diabetes. However, the expression and functional roles of RFX6 in human β cells, especially in pathophysiological conditions, are poorly explored. We demonstrate the presence of RFX6 in adult human pancreatic endocrine cells. Using the recently developed human β cell line EndoC-βH2, we show that RFX6 regulates insulin gene transcription, insulin content, and secretion. Knockdown of RFX6 causes downregulation of Ca(2+)-channel genes resulting in the reduction in L-type Ca(2+)-channel activity that leads to suppression of depolarization-evoked insulin exocytosis. We also describe a previously unreported homozygous missense RFX6 mutation (p.V506G) that is associated with neonatal diabetes, which lacks the capacity to activate the insulin promoter and to increase Ca(2+)-channel expression. Our data therefore provide insights for understanding certain forms of neonatal diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Exocytosis*
  • Homeostasis
  • Humans
  • Insulin / genetics
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Mutation, Missense
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Calcium Channels, L-Type
  • DNA-Binding Proteins
  • Insulin
  • Regulatory Factor X Transcription Factors
  • Rfx6 protein, human
  • Transcription Factors
  • Calcium

Associated data

  • GEO/GSE59049