TY - JOUR

T1 - Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

AU - Colombo, Carlo

AU - Porzio, Ottavia

AU - Liu, Ming

AU - Massa, Ornella

AU - Vasta, Mario

AU - Salardi, Silvana

AU - Beccaria, Luciano

AU - Monciotti, Carla

AU - Toni, Sonia

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Federici, Luca

AU - Pesavento, Roberta

AU - Cadario, Francesco

AU - Federici, Giorgio

AU - Ghirri, Paolo

AU - Arvan, Peter

AU - Iafusco, Dario

AU - Barbetti, Fabrizio

AU - Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (SIEDP)

N1 - Keywords: Amino Acid Sequence; DNA Mutational Analysis; DNA-Binding Proteins; Diabetes Mellitus; Female; Heat-Shock Proteins; Heterozygote; Humans; Infant; Insulin; Male; Molecular Chaperones; Molecular Sequence Data; Mutation; Nuclear Proteins; Pedigree; Proinsulin; Transcription Factors

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1172/JCI33777

DO - 10.1172/JCI33777

M3 - Journal article

C2 - 18451997

VL - 118

SP - 2148

EP - 2156

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -