Variability of isolated autosomal dominant GH deficiency (IGHD II): impact of the P89L GH mutation on clinical follow-up and GH secretion.
Variability of isolated autosomal dominant GH deficiency (IGHD II): impact of the P89L GH mutation on clinical follow-up and GH secretion.
复制标题
孤立性常染色体显性 GH 缺乏症 (IGHD II) 的变异性：P89L GH 突变对临床随访和 GH 分泌的影响。
DOI：
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发表时间：
2005
影响因子：
5.8
通讯作者：
P. Mullis
中科院分区：
文献类型：
--
作者：
S. Salemi;S. Yousefi;K. Baltensperger;I. Robinson;A. Eblé;D. Simon;P. Czernichow;G. Binder;E. Sonnet;P. Mullis
目的
孤立性生长激素缺乏症（IGHD）分为四种不同的家族类型，其中II型IGHD II是常染色体显性遗传形式。基于临床数据，很明显，在导致该疾病的各种GH-1基因改变之间存在广泛的表型变异性。由于特异性错义突变P89 L GH（C6129 T）引起的IGHD II受试者从未有过详细报告，目的是分析这种突变GH形式对其临床随访的影响，并研究其与最常见的错义突变R183 H GH（G6664 A）相比在细胞水平上的作用。
方法
来自4个P89 L GH家系的12例患者与来自5个R183 H GH错义突变家系的17例患者进行了临床比较。此外，共定位的野生型（wt-型）和突变体GH形式进行了研究，在AtT-20细胞，小鼠脑垂体，应用定量共聚焦显微镜分析。使用免疫荧光技术，对细胞的GH和以下细胞器之一进行双重染色：内质网（抗Grp 94）、高尔基体（抗β COP）和分泌颗粒（抗Rab 3a）。此外，GH分泌和细胞活力进行了详细分析。
结果
重要的是，除了生长激素缺乏外，12名P89 L突变GH形式的受试者中有8名出现其他内分泌缺陷，垂体随着时间的推移变得更小（P < 0.05）。在细胞水平上，AtT-20细胞中表达的可变突变体的定量分析揭示了不同程度的共定位，对GH分泌的不同影响，并且因此，对分泌途径的不同影响，这可能是由不同的折叠或聚集问题所引起的，这些问题是通过调节分泌途径进行分选、包装和/或分泌所必需的。
结论
我们的研究结果表明，特定的和详细的分析IGHD II中确定的不同突变可能揭示不同的分泌病理生理机制，并可能提供一个更好的解释与GH错义异构体相关的临床特征的范围。重要的是，P89 L GH患者的研究结果超出了经典的IGHD，并强调需要在IGHD II患者中继续临床警惕其他激素缺乏症的发展。
OBJECTIVE
Four distinct familial types of isolated GH deficiency (IGHD) are classified, of which type II, IGHD II, is the autosomal dominant inherited form. Based on clinical data, it became evident that there is a wide variability in phenotype among the various GH-1 gene alterations leading to the disorder. As subjects suffering from IGHD II caused by the specific missense mutated P89L GH (C6129T) have never been reported in detail, the aim was to analyse the impact of this mutated GH form on its clinical follow-up as well as to study its effect at the cellular level in comparison with the most common missense mutation R183H GH (G6664A).
METHODS
Twelve subjects belonging to four families presenting with P89L GH were clinically compared with 17 subjects from 5 families with the R183H GH missense mutation. Further, co-localization of the wild-type (wt-type) and mutant GH forms was studied in AtT-20 cells, mouse pituitary gland, applying quantitative confocal microscopy analysis. Using immunofluorescent techniques, cells were double stained for GH and one of the following organelles: endoplasmic reticulum (anti-Grp94), Golgi (anti-betaCOP) and secretory granules (anti-Rab3a). In addition, GH secretion and cell viability was analysed in detail.
RESULTS
Importantly, as well as growth hormone deficiency, eight out of twelve subjects with the P89L mutated GH form developed other endocrine deficits and the pituitary gland became smaller over time (P < 0.05). At the cellular level, quantitative analysis of the variable mutants expressed in AtT-20 cells revealed a different extent of co-localization, different effects on GH secretion, and, therefore, a different impact on the secretory pathway which might be caused by different folding or aggregation problems necessary for sorting, packaging and/or secretion through the regulated secretory pathway.
CONCLUSIONS
Our results show that specific and detailed analyses of the different mutations identified in IGHD II may shed light on the different mechanisms of secretory pathophysiology, and may provide a better explanation of the range of clinical features associated with GH missense isoforms. Importantly, the findings in patients with P89L GH extend beyond classical IGHD and stress the need for continued clinical vigilance in IGHD II patients for the development of other hormonal deficiencies.
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DOI：
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