Insulin gene mutations as a cause of permanent neonatal diabetes
| Autor: | Siri Atma W. Greeley, Anna Pluzhnikov, Nancy J. Cox, Emma L. Edghill, Julie Støy, Sarah E. Flanagan, Louis H. Philipson, Honggang Ye, Donald F. Steiner, Jennifer E. Below, Andrew T. Hattersley, Veronica Paz, Rebecca B. Lipton, Gregory M. Lipkind, Sian Ellard, Graeme I. Bell, M. Geoffrey Hayes, Ann-Marie Patch |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Heterozygote Protein Folding medicine.medical_specialty Preproinsulin Potassium Channels Genetic Linkage Receptors Drug medicine.medical_treatment Molecular Sequence Data Mutation Missense Gene mutation Biology Sulfonylurea Receptors medicine.disease_cause Models Biological Diabetes mellitus genetics Neonatal diabetes mellitus Internal medicine Diabetes Mellitus medicine Humans Insulin Amino Acid Sequence Potassium Channels Inwardly Rectifying Protein Precursors Proinsulin Mutation Multidisciplinary Infant Newborn Infant Biological Sciences Permanent neonatal diabetes mellitus medicine.disease Pedigree Endocrinology ATP-Binding Cassette Transporters Female |
| Zdroj: | Støy, J, Edghill, E L, Flanagan, S E, Ye, H, Paz, V P, Pluzhnikov, A, Below, J E, Hayes, M G, Cox, N J, Lipkind, G M, Lipton, R B, Greeley, S A W, Patch, A-M, Ellard, S, Steiner, D F, Hattersley, A T, Philipson, L H, Bell, G I & Neonatal Diabetes International Collaborative Group 2007, ' Insulin gene mutations as a cause of permanent neonatal diabetes ', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 38, pp. 15040-4 . https://doi.org/10.1073/pnas.0707291104 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0707291104 |
| Popis: | 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 β 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 β 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 β 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. |
| Databáze: | OpenAIRE |
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