The role of G protein-coupled signaling in neurocognitive and psychosocialabnormalities

 描述(申请人提供)：奥尔布赖特遗传性骨营养不良症(AHO)是一种罕见的遗传性疾病，由编码Gs的α链基因GNAS(GαS)的杂合失活突变引起，与身材矮小、拇指短指、皮下骨化和认知缺陷有关。具有母系遗传等位基因GNAS突变的AHO患者表现出对多种激素(如甲状旁腺素、促甲状腺激素、促黄体生成素、卵泡刺激素、促性腺激素释放激素)的抵抗力，以及肥胖，一种称为假性甲状旁腺功能减退症1a型(PHP1a)的变异，这是由于父亲在特定组织中印记GαS转录本。在父系遗传等位基因上有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，这种变异被称为假性假性甲状旁腺功能减退症(PPHP)。尽管PHP1a和PPHP都被描述为表现出认知缺陷，但我们发现，PHP1a患者在学业和社交方面的生活都受到了损害，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Aho中观察到的神经认知和心理社会损害是PHP1a特有的，可能是次要的大脑印记。这项研究的目的有四个方面，并将通过在Aho方面有专长(并在肯尼迪·克里格研究所创建了奥尔布赖特诊所)的Germain-Lee博士，以及在神经认知和心理社会评估方面有专长的Mahone博士和Ramos博士(已婚姓名，斯卡伯勒)建立一个新的合作伙伴关系来检验。首先，我们计划系统地检查患有PHP1a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PHP1a患者和PPHP患者，以确定这些人群中的差异，这些人群以前被认为在这些参数方面是相似的。第三，由于本研究中的患者已经或将要进行DNA和转化的淋巴细胞库和突变分析，我们可以开始将神经认知和心理社会表型与基因分型以及GαS蛋白/消息水平和GαS活性相关联。最后，我们将把这些表型/基因型与荷尔蒙和代谢参数联系起来，提供一个独特的机会，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性。这项研究的总体目标是确定PHP1a和PPHP的神经认知和心理社会表型，并确定印记和G蛋白偶联信号以及基因、性别和内分泌功能在所发现的差异的病因中的作用。这项研究可能揭示PHP1a特有的疾病，从而更具体地说，目标管理，导致这些患者的治疗和生活质量的改善。此外，在PHP1a中发现的特定认知和行为表型可能是普通人群中的重大问题，其机制可能通过研究GNAS印记和G蛋白偶联信号的作用而进一步阐明。

 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.