Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism

J Med Genet. 2015 Sep;52(9):612-6. doi: 10.1136/jmedgenet-2015-103220. Epub 2015 Jun 22.


Background: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus.

Methods: Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (

Results: The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site.

Conclusions: Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life.

Keywords: Diabetes; Molecular genetics; Pancreas and biliary tract.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus / etiology
  • Diabetes Mellitus / genetics*
  • Humans
  • Infant
  • Insulin, Regular, Human / genetics*
  • Introns*
  • Mutation*
  • Sequence Analysis, DNA


  • Insulin, Regular, Human

Supplementary concepts

  • Diabetes Mellitus, Permanent Neonatal