molecular mechanism of abnormal growth hormone action
molecular mechanism of abnormal growth hormone action
批准号:
09470221
负责人:
KAJI Hidesuke
金额:
$1.86万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (B)
财政年份:
1997
资助国家:
日本
项目状态:
已结题
起止时间:
1997 至 1998
中文摘要
(1)在我们的患者中发现了GH-1基因的杂合错义突变R77 C。该突变体GH不仅不能单独刺激酪氨酸磷酸化,而且还抑制了野生型GH作为拮抗剂的活性。尽管患者的等位基因中存在基因组突变,但患者父亲的血清中为何不表达突变型GH,仍存在未解决的问题。为了排除基因组遗传的可能性,我们对其外祖母的GH-1基因进行了基因型调查。由于没有突变,体细胞嵌合体可能是更有可能的原因。(2)我们报道了一种新的杂合供体剪接位点突变的内含子9的GH受体(GHR)基因的同胞谁表现出部分GH不敏感和高血清GH结合蛋白(GHBP)水平。该突变导致剪接异常并产生由277个氨基酸组成的截短的GHR(GHR-277),其缺乏GHR的大部分胞内结构域,包括框1和框2。在本研究中,我们已经在体外表征了GHR-277在COS-7或CHO细胞中表达的功能。Scatchard分析显示,与野生型全长GHR(GHR-fl)相比,GHR-277具有两倍数量的结合位点。表达GHR-277的细胞的培养基中的GHBP水平比表达GHR-fl的细胞中的GHBP水平高约3倍。GHR-277和GHR-f1共转染时,GHR-277对GH诱导的STAT 5酪氨酸磷酸化起显性负效应。这些体外结果将很好地解释我们患者的临床特征。(3)在1例疑似生长激素不敏感综合征患者中,我们发现了一个杂合错义突变C422 F,但对该突变GHR的功能研究并不支持该突变是该患者生长障碍的原因。
英文摘要
(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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Keiji Iida: "Growth hormone(GH)insensitivity syndrome with high serum GH-binding protein levels caused by a hetarozygous splice site mutation of the GH receptor gene producing a lack of interacellular domain" Journal of Chinical Endocrinology & Metabolism
Keiji Iida:“生长激素 (GH) 不敏感综合征,血清 GH 结合蛋白水平升高,由 GH 受体基因的杂合剪接位点突变导致细胞间结构域缺乏”,《中国内分泌学杂志》
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通讯作者:
Hidesuke Kaji: "Novel compound heterozygous mutations of grouth hormoue(GH)receptor gene in a patient with GH insensitivily syndrome" Journal of Clinical Endocrinology & Metabolism. 82・11. 3705-3709 (1997)
Hidesuke Kaji:“GH 不敏感综合征患者的生长激素(GH)受体基因的新型复合杂合突变”临床内分泌与代谢杂志 82・11 3705-3709(1997)。
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Satoko Wada: "Characterization of GH3 cells overcxpyessing basic fibroblast grouth facton (FGF-2)" Journal of Neuroendo crnology. 9. 423-430 (1997)
Satoko Wada:“过度表达碱性成纤维细胞生长因子 (FGF-2) 的 GH3 细胞的特征”《神经内科杂志》。
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Hidesuke Kaji: "Cloning and characterization of the 5-flanking region of the human growth hormone secretaiogue receptor gene." Journal of Biological Chemistry. 273・51. 33885-33888 (1998)
Hidesuke Kaji:“人类生长激素分泌受体基因 5 侧翼区域的克隆和表征”,《生物化学杂志》273·51(1998)。
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Takahashi Y,Okimura Y,Mizuno I,Iida K,Takahashi T,Kaji H,Abe H,Chihara K.: "Leptin induces mitogen-activated protein kinase-dependent proliferation of C3H10T1/2 cells." Journal of Biological Chemistry. 272. 12897-12900 (1997)
Takahashi Y、Okimura Y、Mizuno I、Iida K、Takahashi T、Kaji H、Abe H、Chihara K.:“瘦素诱导 C3H10T1/2 细胞的丝裂原激活蛋白激酶依赖性增殖。”
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