2005 Fiscal Year Final Research Report Summary
Analysis of height-determining gene.
| Project/Area Number |
15390324
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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 |
Pediatrics
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| Research Institution | Osaka University |
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Principal Investigator |
OZONO Keiichi Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (20270770)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAJIMA Shigeo Osaka University, Graduate School of Medicine, Associate professor, 医学系研究科, 助教授 (30270771)
ETANI Yuri Osaka University, Graduate School of Medicine, Instructor, 医学系研究科, 助手 (80346220)
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| Project Period (FY) |
2003 – 2005
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| Keywords | short stature / overgrowth / gene trap / PTPN11 / skeletal dysplasia / progeria / glucocorticoid / SHOX |
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| Research Abstract |
We attempted to identify genes which are involved in proliferation and differentiation of chondrocytes because it is likely that such genes affect height. In addition, we examined phenotype and genotype correlation in diseases characterized with short stature. First, we applied a gene-trap approach in the murine mesenchymal cell line ATDC5, and obtained many trap clones with impaired differentiation. Among them, trapped genes were identified to encode p85alpha, subunit of phosphatidylinositide 3-kinase (PI3K) and nuclear factor I-B (NFIB), a transcriptional factor. Trapped clones in which functions of PI3K or NFIB were impaired showed abnormal differentiation of chondrocytes. These result suggest that these genes are candidates of height-determining genes. Hypochondroplasia is caused by a mutation of the fibroblast growth factor receptor 3 (FGFR3) gene and show phenotype milder than achondroplasia. A mutation of the gene, N540K, was found in 3 patients with hypochondroplasia. Gene analysis of FGFR3 is useful to identify hypochondroplasia, leading to the treatment of patients with growth hormone (GH). Compound heterozygous mutation was found in the ZMPSTHE24 gene in sibling cases of mandibuloacral dysplasia. Eight mutations were found in the PTPN11 gene in patients with Noonan syndrome. We analyzed the function of SHP-2 encoded by PTPN11 and obtained results which suggest the correlation between the activity of SHP-2 and the degree of short stature. ESCO2 was firstly identified as a gene responsible for Roberts syndrome which showed very short extremities. The polymorphism of the cAMP-response element binding protein-binding protein (CBP) gene was correlated to susceptibility of glucocorticoid in patients with osteonecrosis.
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