title: RFX6 regulates insulin secretion by modulating Ca2+ homeostasis in human β cells.
abstract: 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.
authors.affiliation: INSERM, U1016, Institut Cochin, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
authors.forename: Vikash
authors.initials: V
authors.lastname: Chandra
authors.affiliation: INSERM, U1016, Institut Cochin, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Albagli-Curiel
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LE, UK.
authors.forename: Benoit
authors.initials: B
authors.lastname: Hastoy
authors.affiliation: Departement of Development and Stem Cells Program, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch 67404, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Piccand
authors.affiliation: CNRS, UMR8104, Institut Cochin, Paris 75014, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Randriamampita
authors.affiliation: CNRS, UMR8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille 59019, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Vaillant
authors.affiliation: Department of Genetics, Robert-Debré Hospital, Paris 75019, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: INSERM, U1016, Institut Cochin, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Hospital, IMAGINE Affiliate, Paris 75015, France.
authors.forename: Kanetee
authors.initials: K
authors.lastname: Busiah
authors.affiliation: CNRS, UMR8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille 59019, France; Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: CNRS, UMR8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille 59019, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LE, UK.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.affiliation: INSERM, U1016, Institut Cochin, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Hospital, IMAGINE Affiliate, Paris 75015, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.affiliation: INSERM, U1016, Institut Cochin, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France. Electronic address: raphael.scharfmann@inserm.fr.
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005089:Exocytosis; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D020125:Mutation, Missense; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D004268:DNA-Binding Proteins; D007328:Insulin; D000071701:Regulatory Factor X Transcription Factors; C547964:Rfx6 protein, human; D014157:Transcription Factors; D002118:Calcium