The HNF-related transcription cascade in maturity-onset diabetes of the young.
| Project/Area Number |
11671104
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Tohoku University |
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Principal Investigator |
HINOKIO Yoshinori Tohoku University, University Hospital, Research Associate, 医学部・附属病院, 助手 (10282071)
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| Co-Investigator(Kenkyū-buntansha) |
HIRAI Masashi Tohoku University, University Hospital, Research Associate, 医学部・附属病院, 助手 (80312578)
SUZUKI Susumu Tohoku University, University Hospital, Lecturer, 医学部・附属病院, 講師 (70216399)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | MODY / HNF / gene mutations / 糖尿病 / MODY |
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| Research Abstract |
Recent genetic studies have shown that maturity-onset diabetes of the young (MODY) is a heterogeneous disorder that can result from mutations in the hepatocyte nuclear factor (HNF)-1α/MODY3, 1β/MODY5, 4α/MODY1 and glucokinase/MODY2 genes. An upstream regulators of HNF-4α expression could be necessary for normal pancreatic β cell function and metabolism. On the other hands, HNF-3β, which is an upstream regulator of the HNF cascade, is believed to play an important role in the expression of essential genes in pancreatic islet functioning. We screened the human HNF-3β gene for mutations in Japanese subjects with early onset NIDDM/MODY of unknown cause and examined the relationship between HNF-3β and the promoter activities of HNF-1α and HNF-4α. We have screened the 3 exons of HNF-3β gene, flanking introns and minimal promoter region for mutations in a group of 70 unrelated Japanese subjects with early-onset NIDDM/MODY of unknown cause and 20 subjects with IDDM.Eight nucleotide substitutions were noted in HNF-3β gene, of which one resulted in the mutation of a conserved serine residue, Ser109 (AGC) to Asn (AAC) and another resulted in the mutation of alanine residue, Ala328 (GCG) to Val (GTG). The latter mutation was also observed in the sample of her mother. In HNF-1α gene, we recognized one mutation of arginine residue, Arg244 (AGA) to Ser (AGT), located in DNA binding homeodomain. The functional study showed that HNF-3β stimulated both of the HNF-1α and HNF-4α promoter activities and that S109N mutant decreased the HNF-1α promoter activity (p<0.05). These facts indicates HNF is highly involved in the development of early-onset diabetes including type1 diabetes and may be one of causes of early-onset diabetes in Japanese.
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Report
(3 results)
Research Products
(16 results)
