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

Carlo Colombo; Ottavia Porzio; Ming Liu; Ornella Massa; Mario Vasta; Silvana Salardi; Luciano Beccaria; Carla Monciotti; Sonia Toni; Oluf Pedersen; Torben Hansen; Luca Federici; Roberta Pesavento; Francesco Cadario; Giorgio Federici; Paolo Ghirri; Peter Arvan; Dario Iafusco; Fabrizio Barbetti; Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (SIEDP)

doi:10.1172/JCI33777

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

Carlo Colombo, Ottavia Porzio, Ming Liu, Ornella Massa, Mario Vasta, Silvana Salardi, Luciano Beccaria, Carla Monciotti, Sonia Toni, Oluf Pedersen, Torben Hansen, Luca Federici, Roberta Pesavento, Francesco Cadario, Giorgio Federici, Paolo Ghirri, Peter Arvan, Dario Iafusco, Fabrizio Barbetti, Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (SIEDP)

Department of Biomedical Sciences

158 Citations (Scopus)

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.

Original language	English
Journal	Journal of Clinical Investigation
Volume	118
Issue number	6
Pages (from-to)	2148-56
Number of pages	8
ISSN	0021-9738
DOIs	https://doi.org/10.1172/JCI33777
Publication status	Published - 2008

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Colombo, C., Porzio, O., Liu, M., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., Hansen, T., Federici, L., Pesavento, R., Cadario, F., Federici, G., Ghirri, P., Arvan, P., Iafusco, D., Barbetti, F., & Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (SIEDP) (2008). Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. Journal of Clinical Investigation, 118(6), 2148-56. https://doi.org/10.1172/JCI33777

Colombo, C, Porzio, O, Liu, M, Massa, O, Vasta, M, Salardi, S, Beccaria, L, Monciotti, C, Toni, S, Pedersen, O, Hansen, T, Federici, L, Pesavento, R, Cadario, F, Federici, G, Ghirri, P, Arvan, P, Iafusco, D, Barbetti, F & Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (SIEDP) 2008, 'Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus', Journal of Clinical Investigation, vol. 118, no. 6, pp. 2148-56. https://doi.org/10.1172/JCI33777

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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.",

author = "Carlo Colombo and Ottavia Porzio and Ming Liu and Ornella Massa and Mario Vasta and Silvana Salardi and Luciano Beccaria and Carla Monciotti and Sonia Toni and Oluf Pedersen and Torben Hansen and Luca Federici and Roberta Pesavento and Francesco Cadario and Giorgio Federici and Paolo Ghirri and Peter Arvan and Dario Iafusco and Fabrizio Barbetti and {Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (SIEDP)}",

note = "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",

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doi = "10.1172/JCI33777",

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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

SN - 0021-9738

VL - 118

SP - 2148

EP - 2156

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 6

ER -

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

Abstract

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