title: Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.
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.
authors.affiliation: Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA.
authors.forename: David
authors.initials: D
authors.lastname: Carmody
authors.affiliation: Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Honggang
authors.initials: H
authors.lastname: Ye
authors.affiliation: Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Perrone
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA.
authors.forename: G
authors.initials: G
authors.lastname: Alkorta-Aranburu
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Highland
authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Hanis
authors.affiliation: Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.affiliation: Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Bell
authors.affiliation: Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Siri Atma W
authors.initials: SA
authors.lastname: Greeley
mesh_terms: D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics*; D006801:Humans; D007223:Infant; D061386:Insulin, Regular, Human / Q000235:genetics*; D007438:Introns; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: D061386:Insulin, Regular, Human
keywords: Diabetes; Molecular genetics; Pancreas and biliary tract