Detalle Publicación


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

Autores: Carmody, D.; Park, S. Y.; Ye, H.; Perrone, M. E.; Alkorta Aranburu, Gorka; Highland, H. M.; Hanis, C.L.; Philipson, L. H.; Bell, G. I.I; Greeley, S. A.
ISSN: 0022-2593
Volumen: 52
Número: 9
Páginas: 612 - 616
Fecha de publicación: 2015
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 ß 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 ß 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.