|Budget Amount *help
¥3,100,000 (Direct Cost : ¥3,100,000)
Fiscal Year 1999 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1998 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1997 : ¥1,800,000 (Direct Cost : ¥1,800,000)
Serum mannan-binding protein (MBP), a C-type animal lectin specific for mannose/N-acethylglucosamine, has been isolated from various mammalian sera. MBP is a member of the collectin (collagen-like lectin) and plays an important role in the first-line host defense during the early stage of a disease or infection.
1. In order to elucidate the mechanism underlying the wide intra-and interracial variety in the MBP serum level, we have studied the transcriptional regulation of human MBP. Rapid amplification of cDNA ends analysis of Hep G2 RNA indicated the presence of a novel exon, designated as "exon 0", upstream of previously identified exon. Promoter analysis involving a luciferase assay vector revealed that the tran-script starting from exon 1 predominates over that starting from exon 0. In addition, a hepatocyte-specific nuclear factor (HNF)-3, which is known to control the expression of hepatocyte-specific genes, upreulates the transcription of human MBP from exon 1, while a glucocorti
coid, which is known to upregulate acute phase proteins, markedly suppresses MBP transcription.
2. Recently, it was reported that a low serum MBP concentration is associated with a common opsonic defect and causes frequent unexplained infections in infants. The patients were homo-or heterozygous for a codon 52, 54 or 57 mutation in the collagen-like region and prevents the assembly of MBP higher oligo-mers. A population study has also shown that the frequency of the opsonic defect nearly corresponds to that of mutant alleles. We studied the metabolic properties of the normal and Gly54 to Asp mutant MBPs in mouse plasma. The radiolabeled normal MBP was found to have a half-life of about 6h, while that of the mutant MBP was almost half as long. These results explain in part the low serum concentration of the mutant MBP.
3. Recently, polymorphisms were found to occur in the promoter region at two positions. Functional promoter analysis indicated that three haplotype variants as to these positions, HY, LY and LX, exhibit high, medium and low promoter activity, respectively, in accordance with the results of a previous population study.