Lauber-Biason
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Endokrinologie/Diabetologie, Abteilung » Prof. Dr. Eugen Schönle » Lauber-Biason
Completed research project
| Title / Titel | Monogenetic Forms of Diabetes Mellitus as a Model to Study Pancreatic Physiology | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | The study of the molecular basis of Mendelian types of diabetes-related disorders, such as maturity onset diabetes of the young (MODY), severe insulin resistance and Wolcott-Rallison syndrome has improved our knowledge of factors involved in the regulation of pancreatic ƒÒ-cell function. Some clinical entities, as for instance the Wolcott-Rallison syndrome provide additional intriguing insights into the relation between glucose homeostasis and protein translation control. We The Wolcott-Rallison syndrome (WRS) is an autosomal recessive disorder characterized by neonatal or early infancy type 1 diabetes mellitus, epiphyseal dysplasia and growth retardation. Mutations in the EIF2AK3 gene, encoding the Eukaryotic Initiation Factor 2ƒÑ-kinase 3 , have been found in WRS patients. We described a girl who came to our attention at two months of age with severe hypertonic dehydration and diabetic ketoacidosis. A diagnosis of type 1 diabetes was made and insulin treatment initiated. Growth retardation and microcephaly were also present. Anti-islet cell autoantibodies were negative and mitochondrial diabetes was excluded. Imaging revealed a hypoplastic pancreas and typical signs of spondylo-epiphyseal dysplasia. The diagnosis of Wolcott-Rallison syndrome was therefore made at age 5. Sequencing analysis of her EIF2AK3 gene revealed the presence of a homozygous T to C exchange in exon 13 leading to the missense Serine 877 Proline mutation. The mutated kinase, although it partly retains the ability of autophosphorylation, is unable to phosphorylate its natural substrate, eIF2ƒÑ. This is the first case in whom the pathophysiological role of EIF2AK3 deficiency in WRS is confirmed at the molecular level. Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans and indicate EIF2AK3 as possible target for therapeutical intervention in diabetes mellitus. Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of diseases characterized by nonketotic diabetes mellitus, an autosomal dominant mode of inheritance, an onset usually before 25 years and often in childhood and adolescence, and a primary defect in function of the ƒÒ-cells of the pancreas. MODY results from heterozygote mutations in the genes encoding the glycolytic enzyme glucokinase (MODY2), and the transcription factors hepatocyte nuclear factor (HNF)- 4ƒÑ (MODY1), HNF1ƒÑ (MODY3), insulin promoter factor (IPF)-1 (MODY4), HNF1ƒÒ (MODY5), and neurogenic differentiation factor 1 (NEUROD1, MODY6). A precise classification of the MODY type has also prognostic implications, since not all the forms are equally severe, might help the choice of therapy and aid the genetic counseling. We therefore started to collect several cases of non type 1 childhood diabetes and we are presently analyzing them for mutations in the six MODY genes. |
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| Publications / Publikationen | Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ (2002) Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes 51: 2301-2305 | ||||
| Keywords / Suchbegriffe | Diabetes mellitus; MODY | ||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Forschungskredit der Universität Zürich, Others |
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| Duration of Project / Projektdauer | Jan 2002 to Apr 2010 |