1998 Fiscal Year Final Research Report Summary
molecular mechanism of abnormal growth hormone action
| Project/Area Number |
09470221
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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 |
内分泌学
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| Research Institution | Kobe University |
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Principal Investigator |
KAJI Hidesuke Kobe University School of Medicine, Third division, Department of Medicine, lecturer, 医学部, 講師 (90224401)
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| Co-Investigator(Kenkyū-buntansha) |
CHIHARA Kazuo Kobe University School of Medicine, Third division, Department of Medicine, Prof, 医学部, 教授 (00107955)
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| Project Period (FY) |
1997 – 1998
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| Keywords | growth hormone / growth hormone gene / growth hormone binding protein / growth hormone receptor / growth hormone receptor gene / insulin like growth factor / growth failure |
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| Research Abstract |
(1) A heterozygous missense mutation R77C in the GH-1 gene was identified in our patient. This mutant GH not only failed to stimulate tyrosine phosphorylation by itself, but also inhibited the activity of the wild-type GH as an antagonist. There are still unresolved problems why the patient's father did not express the mutant GH in his serum despite the presence of a genomic mutation in his allele. To exclude the possibility of genomic implinting, we investigated the genotype of GH-1 gene in his grand mother. Since there was no mutation, somatic mosaicism may be more likely cause.
(2) We have reported a novel heterozygous donor splice site mutation in intron 9 of the GH receptor (GHR) gene in siblings who showed partial GH insensitivity and high serum GH-binding protein (GHBP) levels. This mutation caused the splicing abnormality and produced the truncated GHR consisting of 277 amino acids (GHR-277), which lacked most of the intracellular domain of GHR, including both box 1 and 2. in this study we have characterized the function of GHR-277 expression in COS-7 or CHO cells in vitro. Scatchard analysis revealed that GHR-277 possessed twice the number of binding sites compared to wild-type full-length GHR (GHR-fl). The GHBP level in culture medium of GHR-277-expressing cells was approximately 3 times higher than that in GHR-fl expressing cells. The ligand induced internalization was significantly reduced comapred with that of GHR-fl. Moreover, in GH-induced tyrosine phosphorylation of STAT5, GHR-277 exerted a dominant negative effect when GHR-277 and GHR-fl were cotransfected. These in vitro results would well explain the clinical characteristics in our patients.
(3) In a patient with a possible GH insensitivity syndrome, we found a heterozygous missense mutation C422F.However, functional study of this mutant GHR did not support this mutation as a cause of his growth failure.
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[Publications] Takahashi Y,Shirono H,Arisaka O,Takahashi K,Yagi T,Koga J,Kaji H,Okimura Y,Abe H,Tanaka T,Chihara K.: "Biologically inactive growth hormone caused by an amino acid substitution." Journal of Clinical Investigation. 100. 1159-1165 (1997)
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