The role of G protein-coupled signaling in neurocognitive and psychosocial abnormalities

 描述（由申请人提供）：奥尔布赖特遗传性骨营养不良（AHO）是一种罕见的遗传性疾病，由编码Gs α链（Gαs）的基因GNAS的杂合失活突变引起，与身材矮小、短指（趾）畸形、皮下骨化和认知缺陷相关。在母系遗传等位基因上具有GNAS突变的AHO患者表现出对多种激素（例如PTH、TSH、LH、FSH、GHRH）的抵抗以及肥胖，这是一种称为假性甲状旁腺功能减退症1a型（PHP 1a）的变体，这是由于特定组织中Gαs转录物的父系印记。在父系遗传等位基因上具有GNAS突变的AHO患者具有相同的表型，但没有激素抵抗和明显的肥胖，这是一种称为假甲状旁腺功能减退症（PPHP）的变体。虽然PHP 1a和PPHP都被描述为表现出认知缺陷，但我们发现PHP 1a患者在学业和社交方面受到损害，而PPHP患者则没有。基于大量AHO患者和小鼠模型的初步数据，我们假设在AHO中观察到的神经认知和心理社会障碍是特定于PHP 1a的，可能是继发于大脑中的印记。本研究的目的有四个方面，将通过在AHO方面拥有专业知识的Germain-Lee博士（并在肯尼迪克里格研究所建立了奥尔布赖特诊所）与马宏博士和博士之间建立新的合作来进行检查。拉莫斯（已婚姓名，斯卡伯勒），他们在神经认知和心理社会评估方面拥有专业知识。首先，我们计划系统地检查患有PHP 1a的儿童和成人的神经认知和心理社会功能障碍。其次，我们将比较PHP 1a患者与PPHP患者，以确定这些人群中的差异，这些人群先前被认为在这些参数方面相似。第三，由于本研究中接受检查的患者已经或将要进行DNA和转化淋巴细胞库的储存和突变分析，我们可以开始将神经认知和心理社会表型与基因型以及Gαs蛋白/信息水平和Gαs活性水平相关联。最后，我们将这些表型/基因型与激素和代谢参数相关联，提供了一个独特的机会，将认知和行为与内分泌功能联系起来，并检查潜在的性二型。本研究的总体目标是确定PHP 1a与PPHP的神经认知和心理社会表型，并确定印记和G蛋白偶联信号传导以及基因型、性别和内分泌功能在所发现差异的病因学中的作用。本研究可能揭示PHP 1a特有的疾病，因此更具体地针对管理。从而改善这些患者的治疗和生活质量。此外，在PHP 1a中发现的特定认知和行为表型可能是普通人群中的重要问题，其机制可能通过研究GNAS和G蛋白偶联信号的印记作用进一步阐明。

 DESCRIPTION (provided by applicant): Albright hereditary osteodystrophy (AHO) is a rare genetic disorder caused by heterozygous inactivating mutations in GNAS, the gene encoding the α chain of Gs (Gαs), and is associated with short stature, brachydactyly, subcutaneous ossifications, and cognitive deficits. AHO patients with GNAS mutations on maternally inherited alleles manifest resistance to multiple hormones (e.g. PTH, TSH, LH, FSH, GHRH) as well as obesity, a variant termed pseudohypoparathyroidism type 1a (PHP1a), due to paternal imprinting of Gαs transcripts in specific tissues. AHO patients with GNAS mutations on paternally inherited alleles have the same phenotype but without hormonal resistance and marked obesity, a variant termed pseudopseudo- hypoparathyroidism (PPHP). Although both PHP1a and PPHP have been described as displaying cognitive deficits, we have found that patients with PHP1a lead compromised lives academically and socially, whereas those with PPHP do not. Based on preliminary data in a large cohort of patients with AHO as well as a mouse model, we hypothesize that the neurocognitive and psychosocial impairments observed in AHO are specific to PHP1a and may be secondary to imprinting in the brain. The aims of this study are four-fold and will be examined by forming a new collaboration between Dr. Germain-Lee, who has expertise in AHO (and established the Albright Clinic at Kennedy Krieger Institute), and Drs. Mahone and Ramos (married name, Scarborough), who have expertise in neurocognitive and psychosocial assessments. First, we plan to examine children and adults with PHP1a systematically for neurocognitive and psychosocial dysfunction. Second, we will compare PHP1a patients with PPHP patients in order to define the differences in these populations which have previously been assumed as similar in terms of these parameters. Third, because the patients being examined in this study have had or will have DNA and transformed lymphocytes banked and mutation analyses performed, we can begin to correlate the neurocognitive and psychosocial phenotypes with genotypes as well as with levels of Gαs protein/message levels and Gαs activity. Finally, we will correlate these phenotypes/genotypes with hormonal and metabolic parameters, providing a unique opportunity to link cognition and behavior to endocrine function as well as examine potential sexual dimorphisms. The overall goals of this study are to define the neurocognitive and psychosocial phenotypes in PHP1a versus PPHP and to establish the role of imprinting and G protein-coupled signaling, as well as genotype, sex, and endocrine function, in the etiology of the differences that are found. This study may reveal disorders unique to PHP1a and therefore target management more specifically, leading to improvements in the treatment and quality of life of these patients. In addition, the specific cognitive and behavioral phenotypes found in PHP1a are likely to be significant problems in the general population, and their mechanisms may be further elucidated through investigations of the role of imprinting of GNAS and G protein-coupled signaling.