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

J Clin Invest. 2008 Jun;118(6):2148-56. doi: 10.1172/JCI33777.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • DNA Mutational Analysis
  • DNA-Binding Proteins / biosynthesis*
  • Diabetes Mellitus / genetics*
  • Female
  • Heat-Shock Proteins / biosynthesis*
  • Heterozygote
  • Humans
  • Infant
  • Insulin / genetics*
  • Insulin / physiology*
  • Male
  • Molecular Chaperones / biosynthesis*
  • Molecular Sequence Data
  • Mutation*
  • Nuclear Proteins / biosynthesis*
  • Pedigree
  • Proinsulin / biosynthesis*
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Insulin
  • Molecular Chaperones
  • Nuclear Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Proinsulin
  • molecular chaperone GRP78