Insulin gene mutations as a cause of permanent neonatal diabetes.

St√ły J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI, Neonatal Diabetes International Collaborative Group
Proc Natl Acad Sci U S A. 2007 104 (38): 15040-4

PMID: 17855560 · PMCID: PMC1986609 · DOI:10.1073/pnas.0707291104

We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with beta cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially beta cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of beta cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.

MeSH Terms (22)

Amino Acid Sequence ATP-Binding Cassette Transporters Diabetes Mellitus Female Genetic Linkage Heterozygote Humans Infant Infant, Newborn Insulin Male Models, Biological Molecular Sequence Data Mutation, Missense Pedigree Potassium Channels Potassium Channels, Inwardly Rectifying Proinsulin Protein Folding Protein Precursors Receptors, Drug Sulfonylurea Receptors

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