1997 Fiscal Year Final Research Report Summary
IDENTIFICATION OF THE GENE RESPONSIBLE FOR THE DEVELOPMENT OF FAMILIAL EARLY-ONSET DIABETES MELLITUS (MODY)
| Project/Area Number |
08457627
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human genetics
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| Research Institution | GUNMA UNIVERSITY |
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Principal Investigator |
TAKEDA Jun INSTITUTE FOR MOLECULAR AND CELLULAR REGULATION,GUNMA UNIVERSITY PROFESSOR, 生体調節研究所, 教授 (40270855)
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| Co-Investigator(Kenkyū-buntansha) |
ISUMI Tetsurou INSTITUTE FOR MOLECULAR AND CELLULAR REGULATION,GUNMA UNIVERSITY ASSOCIATE PROFE, 生体調節研究所, 助教授 (00212952)
TAKEUCHI Toshiyuki INSTITUTE FOR MOLECULAR AND CELLULAR REGULATION,GUNMA UNIVERSITY PROFESSOR, 生体調節研究所, 教授 (00109977)
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| Project Period (FY) |
1996 – 1997
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| Keywords | positional cloning / early-onset diabetes mellitus / transcription factor / insulin secretion |
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| Research Abstract |
Maturity-onset diabetes of the young (MODY), a single-gene disorder, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosome 7 (MODY2), 12 (MODY3) and 20 (MODY1) and clinical studies indicate that mutations are associated with abnormal patterns of glucose-stimulated insulin secretion. In this study, MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin 1 gene. Ten exons and flanking introns of the HNF-1alpha gene in Caucasian subjects with MODY3 were amplified by the polymerase chain reaction and direct sequencing of the products. Two frameshift mutations (P291fsinsC,P379fsdelCT), two missense mutations (P447L,R131Q), and two mutations at exon/intron boundary (IVS9nt+1G-A,IVS5nt-2A-G) were identified.Mutations were also identified in three (5.5%) of the 55 unrelated Japanese subjects with IDDM.These mutations are two missense mutations (R272H,R583G) and a frameshift mutation (P291fsinsC). None of these mutations were present in 100 non-diabetic subjects. These results indicate that the HNF-1alpha gene defects could lead to the development of not only MODY but also IDDM,implicating the importance of subclassification of HNF-1alpha-deficient IDDM from a classical type of autoimmune-based (Type 1) IDDM.
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