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
PY - 2008/6/2
Y1 - 2008/6/2
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 β 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 β 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.
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U2 - 10.1172/JCI33777
DO - 10.1172/JCI33777
M3 - Article
C2 - 18451997
AN - SCOPUS:45749104374
VL - 118
SP - 2148
EP - 2156
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -