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R77C。该突变型GH不仅自身不能刺激酪氨酸磷酸化,而且作为拮抗剂抑制了野生型GH的活性。尽管患者的父亲的等位基因存在基因组突变,但他的血清中却没有表达突变的生长激素,这一问题至今仍未得到解决。为了排除基因组暗示的可能性,我们对其祖母的GH-1基因进行了基因型分析。由于没有突变,体细胞嵌合可能是更可能的原因。(2)我们报道了生长激素受体(GHR)基因内含子9的一种新的杂合供体剪接位点突变,这些突变发生在表现出部分生长激素不敏感和高血清GH结合蛋白(GHBP)水平的兄弟姐妹中。该突变导致剪接异常,产生由277个氨基酸组成的截断GHR (GHR-277),缺失了GHR的大部分胞内结构域,包括box 1和box 2。在本研究中,我们在体外鉴定了GHR-277在COS-7或CHO细胞中的表达功能。Scatchard分析显示,GHR-277的结合位点数量是野生型全长GHR (GHR-fl)的两倍。表达ghr -277的细胞培养液中GHBP的水平比表达GHR-fl的细胞培养液中GHBP的水平高约3倍。与GHR-fl相比,配体诱导的内化明显减少。此外,在gh诱导的STAT5酪氨酸磷酸化中,当GHR-277和GHR-fl共转染时,GHR-277发挥了显性的负作用。这些体外实验结果可以很好地解释我们患者的临床特征。(3)在一位可能患有生长激素不敏感综合征的患者中,我们发现了一个杂合错义突变C422F。然而,该突变GHR的功能研究并不支持该突变是其生长失败的原因。
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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