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Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse

Izumi, Tetsuro
Yokota-Hashimoto, Hiromi
Zhao, Shengli
Wang, Jie
Takeuchi, Toshiyuki
Published in Diabetes. 2003, vol. 52, no. 2, p. 409-416
Abstract Autosomal dominant diabetes in the Akita mouse is caused by mutation of the insulin 2 gene, whose product replaces a cysteine residue that is engaged in the formation of an intramolecular disulfide bond. These heterozygous mice exhibit severe insulin deficiency despite coexpression of normal insulin molecules derived from three other wild-type alleles of the insulin 1 and 2 genes. Although the results of our previous study suggested that the mutant proinsulin 2 is misfolded and blocked in the transport from the endoplasmic reticulum to the Golgi apparatus, its dominant negative nature has not been fully characterized. In the present study, we investigated the possible pathogenic mechanisms induced by the mutant proinsulin 2. There is no evidence that the mutant proinsulin 2 attenuates the overall protein synthesis rate or promotes the formation of aberrant disulfide bonds. The trafficking of constitutively secreted alkaline phosphatase, however, is significantly decreased in the islets of Akita mice, indicating that the function of early secretory pathways is nonspecifically impaired. Morphological analysis has revealed that secretory pathway organelle architecture is progressively devastated in the beta-cells of Akita mice. These findings suggest that the organelle dysfunction resulting from the intracellular accumulation of misfolded proinsulin 2 is primarily responsible for the defect of coexisting wild-type insulin secretion in Akita beta-cells.
Keywords Amino Acid SubstitutionAnimalsBase SequenceCHO CellsCricetinaeCysteineCysteine Endopeptidases/metabolismDNA PrimersDiabetes Mellitus, Type 1/ genetics/pathologyEndoplasmic Reticulum/metabolismGenes, DominantGolgi Apparatus/metabolismHeterozygoteIslets of Langerhans/pathology/ physiology/ultrastructureMiceMice, Mutant StrainsMultienzyme Complexes/metabolismMutagenesis, Site-DirectedProinsulin/ genetics/metabolism/secretionProtease Inhibitors/pharmacologyProteasome Endopeptidase ComplexProtein DenaturationProtein FoldingProtein TransportRecombinant Proteins/metabolismTransfection
PMID: 12540615
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IZUMI, Tetsuro et al. Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. In: Diabetes, 2003, vol. 52, n° 2, p. 409-416. doi: 10.2337/diabetes.52.2.409 https://archive-ouverte.unige.ch/unige:8828

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Deposited on : 2010-07-12

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