Investigators found 10 missense mutations, which potentially trigger ER stress and cause pancreatic beta cells to die.
A group of researchers found 10 genetic mutations in the insulin gene, which they believe causes permanent neonatal diabetes. This is the first time that an insulin mutation has been connected to severe diabetes with onset early in life, the scientists report.
“This is a novel and potentially treatable cause of diabetes in infants,” says study author Louis Philipson, M.D., Ph.D., professor of medicine at the University of Chicago. Along with the Peninsula University, 21 patients from 16 families were analyzed.
“It’s exciting because each of these patients has one normal insulin gene as well as one mutated gene. If we could detect the disease early enough and somehow silence the abnormal gene or just protect insulin-producing cells from the damage caused by misfolding, we might be able to preserve or restore the patient’s own insulin production.”
In one family with four affected individuals, tests for known mutations were negative. A combination of linkage studies and candidate-gene testing, however, traced the problem to an abnormal insulin gene. Further analysis identified a total of 10 insulin gene mutations in patients from 15 other families.
All 10 are missense mutations, which code for a different amino acid than the one normally found at that position. Such variations can prevent a protein from folding into its customary shape.
Dysfunctional proteins are usually dismantled by the endoplasmic reticulum (ER). Prolonged demands on this system, however, can cause chronic endoplasmic reticulum stress that can lead eventually to cell death.
The authors postulate that misfolded insulin and its precursors could induce prolonged ER stress, causing the insulin-producing pancreatic beta cells to die.
The study will be published in the September 18, 2007, issue of the Proceedings of the National Academy of Sciences and is published early online.