[IPu] Fw: [IPp] Mutations In The Insulin Gene Can Cause Neonatal Diabetes
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Mutations In The Insulin Gene Can Cause Neonatal Diabetes
*Science Daily <http://www.sciencedaily.com/> * Mutations in the insulin
gene can cause permanent neonatal diabetes, an unusual form of diabetes that
affects very young children and results in lifelong dependence on insulin
injections, report researchers from the University of Chicago and Peninsula
University (Exeter, UK) in the Proceedings of the National Academy of
Although abnormal insulin has been associated with milder cases of type 2
diabetes since the discovery of "insulin Chicago" in 1979, this is the first
time that an insulin mutation has been connected to severe diabetes with
onset early in life.
The researchers describe 10 mutations, found in 21 patients from 16
families. They suspect that the mutations alter the way insulin folds
its synthesis. They suggest that these improperly folded proteins interfere
with other cellular processes in ways that eventually kill the cells that
"This is a novel and potentially treatable cause of diabetes in infants,"
said study author Louis Philipson, MD, PhD, professor of medicine at the
University of Chicago. "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."
The effort to learn more about possible genetic causes of neonatal diabetes
followed a flurry of publicity last September. Philipson and colleagues at
the *University of Chicago* -- using a protocol developed by co-author
Andrew Hattersley, MD, Professor of *Molecular Medicine at Peninsula
University* -- were able to wean a young diabetes patient with a known,
treatable mutation in an ion channel protein essential for insulin
secretion, off of insulin. This was one of the first such cases in the
Media coverage of that case and outreach by the Juvenile Diabetes Research
Foundation stimulated parents of other children diagnosed as infants with
type-1 diabetes to contact one of the two centers to request genetic
testing. Testing at the University of Chicago uncovered more than a dozen
patients with the same treatable mutation.
*The publicity also brought calls from the families of more than 70
who had been diagnosed with diabetes at less than one year of age but who,
as it turned out, did not have a known mutation.*
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 tests
identified a total of 10 different insulin-gene mutations in patients from
15 other families.
All ten are "missense" mutations; they code for a different amino acid than
the one normally found at that position. Such mutations can prevent a
protein from folding into its customary shape.
Dysfunctional proteins are usually dismantled by the endoplasmic reticulum,
an organelle that can detect misfolded proteins and degrade them. 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
Treatments aimed at reducing ER stress "might result in better beta cell
survival," they suggest. "This could partially ameliorate the diabetic state
if secretion resulting from the normal insulin allele could be better
"Insulin mutations are an important cause of neonatal diabetes," say the
authors, accounting for about 20 percent of cases of this rare disorder.
Most cases tied to insulin mutation were diagnosed in the first six months
of life, with an average age at diagnosis of only 13 weeks. Three of the
cases were diagnosed between 6 months and one year after birth.
Neonatal diabetes is considered a genetic disorder by many, said Philipson.
Mutations in known genes explain 50 to 60 percent of cases and research
teams in the US and Europe are trying to identify a genetic cause of
diabetes in the remaining patients.
Even though neonatal diabetes is a rare disease, identification of genes
causing it has lead to important knowledge about pancreatic development and
function, as well as to more precise diagnosis and improved management of
In 2001, Graeme Bell, PhD, the Louis Block Distinguished Service Professor
of Medicine and Human Genetics at the University of Chicago and a co-author
of this paper, discovered one of the first gene defects associated with
neonatal diabetes, mutation of the gene for glucokinase, an enzyme that
helps regulate blood-sugar levels. Bell also discovered several genes that
cause other forms of monogenic diabetes and the first gene associated with
Type 2 diabetes.
In 1979, co-author Donald Steiner, MD, the A.N. Pritzker Professor in
Biochemistry & Molecular Biology and a member of the Howard Hughes Medical
Institute at the University of Chicago, was a member of the team that
discovered the first mutant insulin, known as "insulin Chicago."
The Wellcome Trust funded the work in Exeter and the National Institutes of
Health and the Kovler Foundation supported the work done in Chicago.
Additional authors of the paper include Julie Stxy, Honggang Ye, Veronica
Paz, Anna Pluzhnikov, Jennifer Below, Geoffrey Hayes, Nancy Cox, Gregory
Lipkind, Rebecca Lipton and Siri Atma Greeley of the University of Chicago,
and Emma Edghill, Sarah Flanagan, Ann-Marie Patch and Sian Ellard of
Peninsula University, Exeter.
Reference: PNAS, Sept. 18 print issue (pp. 15040-15044, Issue 38, Volume
104) published early online.
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