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

G 蛋白偶联信号在神经认知和心理社会异常中的作用

基本信息

批准号：
9234576
负责人：
EMILY L GERMAIN-LEE
金额：
$ 21.14万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-10-28 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9234576
关键词：
Adult Alleles Behavior Behavioral Brain Child Childhood Clinic Cognition Cognitive Cognitive deficits Collaborations Coupled DNA Data Development Disease Disease Management Endocrine Endocrinologist Etiology Frameshift Mutation Functional disorder G-substrate GNAS gene GTP-Binding Proteins General Population Genes Genotype Gnas protein Goals Hereditary Disease Home environment Hormonal Hormones Human Hypothalamic structure Impairment Inherited Institutes Investigation Lead Link Lymphocyte Metabolic Missense Mutation Mutation Mutation Analysis Names Neurocognitive Neurocognitive Deficit Neurodevelopmental Disorder Nonsense Mutation Obesity Patients Phenotype Physiologic Ossification Physiological Pituitary Gland Play Population Proteins Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Psychosocial Assessment and Care Quality of life Resistance Role Secondary to Severities Signal Transduction Somatotropin-Releasing Hormone Tissues Transcript Variant base clinical care cohort genotypic sex growth hormone deficiency imprint mouse model paternal imprint psychosocial public health relevance sexual dimorphism social subcutaneous

项目摘要

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.

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 GNAS 杂合失活突变引起，GNAS 是编码 Gs α 链 (Gαs) 的基因，与身材矮小、短指、皮下骨化和认知缺陷有关。母系遗传等位基因上带有 GNAS 突变的 AHO 患者表现出对多种激素（例如 PTH、TSH、LH、FSH、GHRH）的抵抗性以及肥胖（一种称为假性甲状旁腺功能减退症 1a 型 (PHP1a) 的变异体），这是由于特定组织中 Gαs 转录本的父系印记所致。父系遗传等位基因上带有 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，这种变异称为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 患者的学业和社交生活受到损害，而 PPHP 患者则不然。根据大量 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伤是 PHP1a 特有的，并且可能继发于大脑印记。这项研究的目标有四个方面，将通过在 AHO 领域拥有专业知识的 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）和 Drs. Germain-Lee 之间建立新的合作来进行检验。 Mahone 和 Ramos（婚名：Scarborough），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 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 患者与 PPHP 患者，以确定这些人群中的差异，之前这些人群在这些参数方面被认为是相似的。第三，由于本研究中接受检查的患者已经或将要储存 DNA 和转化淋巴细胞并进行突变分析，因此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 活性关联起来。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，并检查潜在的性别二态性。本研究的总体目标是定义 PHP1a 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。这项研究可能揭示 PHP1a 特有的疾病，从而更具体地进行针对性治疗，从而改善这些患者的治疗和生活质量。此外，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，并且通过研究GNAS印记和G蛋白偶联信号传导的作用可以进一步阐明其机制。