Continued lessons from theINSgene: an intronic mutation causing diabetes through a novel mechanism

Abstract

Background Diabetes in neonates usually has a monogenic etiology; 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 characterization 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 beta 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. Conclusion Dominant INS mutations cause diabetes via a mutated translational product causing ER stress. We describe a novel mechanism of diabetes, without beta 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.

Congenital forms of diabetes: the beta-cell and beyond

“…By studying a case with a novel deep intronic homozygous mutation ( INS : c.187+241G>A), a novel mechanism of diabetes was discovered [27]. This also supports how regulatory regions that are often not covered by genetic testing, such as deep introns, may be important in finding a genetic cause for the remaining ‘unknown’ infancy-onset cases.…”

Pathway Analysis Based on a Genome-Wide Association Study of Polycystic Ovary Syndrome

“…INS was observed in all three top ranking pathways associated with PCOS. Previous studies showed an association of this gene with insulin resistance, obesity and type 2 diabetes through variation of the VNTR (variable number of tandem repeats) locus at class III allele [ 33 – 35 ]. INS was also associated with anovulation in PCOS, although there are conflicting studies [ 36 – 38 ].…”

Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features

“…The most common mutations are autosomal dominantly inherited heterozygous missense mutations that generate improperly folded proteins which are likely held in the endoplasmic reticulum, leading to beta-cell stress, and eventually beta-cell death [23]. A recent case of a novel homozygous intronic mutation describes a different mechanism of action via a mutated translational product without beta-cell death [24]. While most mutations in the INS gene cause diabetes onset within the first year of life, certain mutations can cause a more mild dysfunction with later diabetes onset and a more MODY-like phenotype [25].…”