Identification and Functional Analysis of Mutations in FAD-Binding Domain of Mitochondrial Glycerophosphate Dehydrogenase in Caucasian Patients with Type 2 Diabetes Mellitus
| Autor: | Monica Gudayol, Albert Morales, E F Usac, José C. Fernández-Checa, Ramon Gomis, Josep Vidal, Marta E Fabregat, Anna Novials |
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| Rok vydání: | 2001 |
| Předmět: |
Male
DNA Complementary Xenopus Endocrinology Diabetes and Metabolism Glycerolphosphate Dehydrogenase Type 2 diabetes Mitochondrion Biology medicine.disease_cause Cohort Studies Endocrinology Complementary DNA medicine Animals Humans Gene Cells Cultured Aged chemistry.chemical_classification Mutation Mutagenesis Type 2 Diabetes Mellitus Middle Aged medicine.disease Molecular biology Mitochondria Protein Structure Tertiary Enzyme Diabetes Mellitus Type 2 chemistry Flavin-Adenine Dinucleotide Oocytes Female |
| Zdroj: | Endocrine. 16:39-42 |
| ISSN: | 0969-711X |
| DOI: | 10.1385/endo:16:1:39 |
| Popis: | Ca2+-responsive mitochondrial FAD-linked glycerophosphate dehydrogenase (mGPDH) is a key component of the pancreatic beta-cell glucose-sensing device. The purpose of this study was to examine the association of mutations in the cDNA coding for the FAD-binding domain of mGPDH and to explore the functional consequences of these mutations in vitro. To investigate this association in type 2 diabetes mellitus, we studied a cohort of 168 patients with type 2 diabetes and 179 glucose-tolerant control subjects of Spanish Caucasian origin by single-stranded conformational polymorphism analysis. In vitro site-directed mutagenesis was performed in the mGPDH cDNA sequence to reproduce those mutations that produce amino acid changes in a patient with type 2 diabetes. We detected mutations in the mGPDH FAD-binding domain in a single patient, resulting in a Gly to Arg amino acid change at positions 77, 78, and 81 and a Thr to Pro at position 90. In vitro expression of the mutated constructs in Xenopus oocytes resulted in a significantly lower enzymatic activity than in cells expressing the wild-type form of the enzyme. Our results indicate that although mutations in the mGPDH gene do not appear to have a major role in type 2 diabetes mellitus, the reduction in mGPDH enzymatic activity associated with the newly described mGPDH mutations suggests that they may contribute to the disease in some patients. |
| Databáze: | OpenAIRE |
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