title: Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus.
abstract: Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.
authors.affiliation: Laboratory of Molecular Endocrinology and Metabolism, Bambino Gesù Children's Hospital, Scientific Institute and Department of Internal Medicine, University of Tor Vergata, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Colombo
authors.forename: Ottavia
authors.initials: O
authors.lastname: Porzio
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Ornella
authors.initials: O
authors.lastname: Massa
authors.forename: Mario
authors.initials: M
authors.lastname: Vasta
authors.forename: Silvana
authors.initials: S
authors.lastname: Salardi
authors.forename: Luciano
authors.initials: L
authors.lastname: Beccaria
authors.forename: Carla
authors.initials: C
authors.lastname: Monciotti
authors.forename: Sonia
authors.initials: S
authors.lastname: Toni
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Luca
authors.initials: L
authors.lastname: Federici
authors.forename: Roberta
authors.initials: R
authors.lastname: Pesavento
authors.forename: Francesco
authors.initials: F
authors.lastname: Cadario
authors.forename: Giorgio
authors.initials: G
authors.lastname: Federici
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghirri
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.forename: Dario
authors.initials: D
authors.lastname: Iafusco
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Barbetti
mesh_terms: D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003920:Diabetes Mellitus / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007328:Insulin / Q000235:genetics* / Q000502:physiology*; D008297:Male; D018832:Molecular Chaperones / Q000096:biosynthesis*; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010375:Pedigree; D011384:Proinsulin / Q000096:biosynthesis*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007328:Insulin; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D011384:Proinsulin