Evaluation of the biological activity of a growth hormone (GH) mutant (R77C) and its impact on GH responsiveness and stature.
Evaluation of the biological activity of a growth hormone (GH) mutant (R77C) and its impact on GH responsiveness and stature.
复制标题
评估生长激素 (GH) 突变体 (R77C) 的生物活性及其对 GH 反应性和身高的影响。
DOI：
10.1210/jc.2006-2238
复制
发表时间：
2007
期刊：
影响因子：
--
通讯作者：
P. Mullis
中科院分区：
文献类型：
--
作者：
Vibor Petkovic;Amélie Besson;M. Thevis;Didier Lochmatter;A. Eblé;C. Flück;P. Mullis
背景和目标
GH-1 基因中的单个错义突变将密码子 77 从精氨酸 (R) 转换为半胱氨酸 (C)，产生突变型 GH-R77C 肽，该肽被描述为天然 GH 拮抗剂。
设计、环境和患者
在叙利亚家族中鉴定出 GH-R77C/wt-GH 杂合性。指标患者是一名男孩，被转诊评估其身材矮小（-2.5 SD 评分），并诊断出部分 GH 不敏感。他的母亲和祖父也携带相同的突变，并表现出部分 GH 不敏感性和适度的身材矮小。
干预措施和结果
通过研究 GH 受体结合和 Janus 激酶 2/Stat5 通路的激活，对 GH-R77C 进行了功能表征。未发现 wt-GH 和 GH-R77C 之间的结合亲和力和生物活性存在差异。类似地，AtT-20 细胞中表达两种 GH 肽后的细胞活力和增殖是相同的。定量共聚焦显微镜分析显示，wt-GH 和 GH-R77C 与内质网、高尔基体或分泌囊泡的亚细胞共定位程度没有显着差异。此外，研究表明，与 wt-GH 相比，GH-R77C 诱导 GHR/GHBP 基因转录率的能力降低。
结论
GH 受体/GH 结合蛋白表达减少可能是我们患者中发现的部分 GH 不敏感以及生长和青春期发育延迟的可能原因。此外，这组患者值得进一步关注，因为他们可能代表一个独特的临床实体，强调改变的 GH 肽也可能对 GHR/GHBP 基因表达产生直接影响，导致部分 GH 不敏感。
CONTEXT AND OBJECTIVE
A single missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C) yields a mutant GH-R77C peptide, which was described as natural GH antagonist.
DESIGN, SETTING, AND PATIENTS
Heterozygosity for GH-R77C/wt-GH was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SD score) and partial GH insensitivity was diagnosed. His mother and grandfather were also carrying the same mutation and showed partial GH insensitivity with modest short stature.
INTERVENTIONS AND RESULTS
Functional characterization of the GH-R77C was performed through studies of GH receptor binding and activation of Janus kinase 2/Stat5 pathway. No differences in the binding affinity and bioactivity between wt-GH and GH-R77C were found. Similarly, cell viability and proliferation after expression of both GH peptides in AtT-20 cells were identical. Quantitative confocal microscopy analysis revealed no significant difference in the extent of subcellular colocalization between wt-GH and GH-R77C with endoplasmic reticulum, Golgi, or secretory vesicles. Furthermore studies demonstrated a reduced capability of GH-R77C to induce GHR/GHBP gene transcription rate when compared with wt-GH.
CONCLUSION
Reduced GH receptor/GH-binding protein expression might be a possible cause for the partial GH insensitivity with delay in growth and pubertal development found in our patients. In addition, this group of patients deserves further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity.
重新审视 IGF-I 生成测试：GH 敏感性的标志。
DOI：
10.1210/jcem.86.11.8019
发表时间：
2001
期刊：
The Journal of clinical endocrinology and metabolism.
影响因子：
--
作者：
Buckway,CK;Guevara-Aguirre,J;Pratt,KL;Burren,CP;Rosenfeld,RG
通讯作者：
Rosenfeld,RG
人生长激素在体内的血浆运输。
DOI：
10.1210/jcem-71-2-470
发表时间：
1990
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
Baumann,G;Vance,ML;Shaw,MA;Thorner,MO
通讯作者：
Thorner,MO
影响因子：
4.8
作者：
BAUMANN, G;AMBURN, K;SHAW, MA
通讯作者：
SHAW, MA