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

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

Author information

1
Departments of Medicine and Pediatrics, Section of Adult and Pediatric Endocrinology, Diabetes, & Metabolism, The University of Chicago, Chicago, Illinois, USA.
2
Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA.
3
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

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.

KEYWORDS:

Diabetes; Molecular genetics; Pancreas and biliary tract

PMID:
26101329
PMCID:
PMC4744477
DOI:
10.1136/jmedgenet-2015-103220
[Indexed for MEDLINE]
Free PMC Article

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