STUDIES OF HORMONE ACTION IN PATIENTS WITH ALTERED G PROTEIN FUNCTION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 许多激素的作用需要它们与特异性细胞表面受体相互作用，这些受体通过鸟嘌呤核苷酸结合蛋白Gs（由GNAS基因编码）偶联以刺激腺苷酸环化酶。 具有改变的生物活性的激素、受体或Gs分子的表达可导致激素作用的获得或丧失。该协议检查的分子基础改变激素作用的信号转导途径，利用Gs蛋白作为信号转导。这些疾病包括由于Gs的表达或功能改变引起的假性甲状旁腺功能减退1a型（PHP 1a）和McCune Albright综合征，由于GNAS基因甲基化异常引起的假性甲状旁腺功能减退1b型，以及由于钙敏感受体或PTH基因缺陷引起的甲状旁腺功能减退。患者表型的生物化学和临床表征有助于以实验室为基础的方法来阐明疾病的分子机制。具体而言，在PHP 1a中，身材矮小和肥胖是主要的临床问题。 我们评估了PHP 1a患者的临床和内分泌特征，以确定他们是否可能继发于生长激素（GH）缺乏，由于生长激素释放激素的信号转导缺陷，这可能是导致身材矮小和肥胖的原因。事实上，我们已经发现这些患者中大约三分之二是GH缺乏的（Germain-Lee等人，2003; Germain-Lee，2006;和未发表的结果）。目前，我们已完成了34例受试者的筛选，并在22例受试者中发现了GH缺乏的证据。其中一些受试者目前正在接受人重组GH的GH治疗试验。GH治疗初步显示以下一项或多项改善：线性生长速度（儿童）;最终成人身高;体重参数;肥胖症;血脂谱;和骨密度。 因此，GH可改善该患者人群的生活质量和总体健康状况。PHP 1a是奥尔布赖特遗传性骨营养不良的一种亚型，这是一个更广泛的类别，包括PHP 1a和假性甲状旁腺功能减退症（pseudopeprododohypopathyrophysiological，pseudoPHP）。假性PHP是由引起PHP 1a的GNAS基因中相同的杂合失活突变引起的。虽然PHP 1a和pseudoPHP患者具有相似的表型，但pseudoPHP患者没有激素异常。这种差异的发生是因为父系印记-即，当缺陷等位基因是母系起源，PHP 1a发生与激素异常继发于组织特异性印记在生殖活性组织;当缺陷等位基因是父系起源，pseudoPHP发生没有激素异常。然而，pseudoPHP患者也很短，即使他们不是GH缺乏症。PHP 1a和pseudoPHP的身材矮小部分归因于骨骺的过早融合，最可能继发于由于G-α-s的单倍不足导致的过早软骨细胞分化。我们目前正在研究生长激素缺乏与早熟骨骺融合在身材矮小表型中的影响。 此外，我们计划研究GH在改善PHP 1a患者的线性生长速度和最终成人身高中的作用，这些患者不是GH缺乏症以及pseudoPHP患者（根据定义，他们不是GH缺乏症）。通过增加骨骺融合前的线性生长速度，也可能改善这些非GH缺乏患者人群的最终成人身高。传统上，人们认为pseudoPHP患者也像PHP 1a一样肥胖。我们发现肥胖是PHP 1a比pseudoPHP更突出的特征，并且严重肥胖是PHP 1a特有的特征。 这些发现暗示了在PHP 1a肥胖症的发展中父亲的G-α-s印记（Long等人，出版中）。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The action of many hormones requires their interaction with specific cell surface receptors that are coupled by the guanine nucleotide-binding protein Gs (encoded by the GNAS gene) to stimulation of adenylyl cyclase. Expression of hormones, receptors, or Gs molecules with altered biological activity can result in gain or loss of hormone action. This protocol examines the molecular basis for altered hormone action in signal transduction pathways that utilize Gs protein as a signal transducer. These disorders include pseudohypoparathyroidism type 1a (PHP1a) and McCune Albright syndrome due to altered expression or function of Gs, pseudohypoparathyroidism type 1b due to abnormalities in the methylation of the GNAS gene, and hypoparathyroidism due to defects in the calcium-sensing receptor or PTH gene. Biochemical and clinical characterization of the patient's phenotype facilitates a laboratory-based approach to elucidating the molecular mechanism of disease. Specifically, within PHP1a, short stature and obesity are major clinical concerns. We have evaluated the clinical and endocrine characteristics of patients with PHP1a to determine whether they might have deficient secretion of GH secondary to growth hormone (GH) deficiency due to defective signal transduction of growth hormone-releasing hormone which could be the cause of the short stature and obesity. Indeed, we have found that approximately two-thirds of these patients are GH deficient (Germain-Lee et al., 2003; Germain-Lee, 2006; and unpublished results). At this point in time, we have completed screening of 34 subjects and have found evidence of GH deficiency in 22 subjects. Some of these subjects are currently in a GH treatment trial with human recombinant GH. GH treatment has preliminarily shown an improvement in one or more of the following: linear growth velocities (in children); final adult heights; weight parameters; adiposity; lipid profiles; and bone densities. Therefore, GH may improve the quality of life and overall health in this patient population. PHP1a is a sub-type of Albright hereditary osteodystrophy, a broader category which includes both PHP1a and pseudopseudohypoparathyroidism (pseudoPHP). PseudoPHP results from the same heterozygous inactivating mutations in the GNAS gene which cause PHP1a. Although patients with PHP1a and pseudoPHP have similar phenotypes, those with pseudoPHP do not have hormonal abnormalities. This difference occurs because of paternal imprinting-- ie, when the defective allele is maternal in origin, PHP1a occurs with hormonal abnormalities secondary to tissue-specific imprinting in hormonally active tissues; when the defective allele is paternal in origin, pseudoPHP occurs without hormonal abnormalities. However, pseudoPHP patients are also short even though they are not GH deficient. The short stature in both PHP1a and pseudoPHP is partially contributed to by premature fusion of the epiphyses most likely secondary to premature chondrocyte differentiation due to haploinsufficiency of G-alpha-s. We are currently investigating the impact of GH deficiency versus the premature epiphyseal fusion in the short stature phenotype. In addition, we plan to investigate the role of GH in the improvement of linear growth velocity and final adult height of those patients with PHP1a who are not GH deficient as well as patients with pseudoPHP (who, by definition, are not GH deficient). It is possible that by increasing linear growth velocity prior to epiphyseal fusion, final adult heights could be improved in these non-GH deficient patient populations as well. Classically, it has been thought that pseudoPHP patients are also obese, as in PHP1a. We have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings implicate paternal imprinting of G-alpha-s in the development of the obesity in PHP1a (Long et al, in press).