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Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism
  1. David Carmody1,
  2. Soo-Young Park1,
  3. Honggang Ye1,
  4. Marie E Perrone1,
  5. G Alkorta-Aranburu2,
  6. Heather M Highland3,
  7. Craig L Hanis3,
  8. Louis H Philipson1,
  9. Graeme I Bell1,
  10. Siri Atma W Greeley1
  1. 1Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA
  2. 2Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA
  3. 3Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA
  1. Correspondence to Dr Siri Atma Greeley, Department of Pediatrics, The University of Chicago, 5841 S Maryland Ave, MC 1027, Chicago, Illinois 60637, USA; sgreeley{at}peds.bsd.uchicago.edu.

Abstract

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 (http://monogenicdiabetes.uchicago.edu).

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.

  • Diabetes
  • Molecular genetics
  • Pancreas and biliary tract

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