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

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：
9035448
负责人：
EMILY L GERMAIN-LEE
金额：
$ 12.27万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
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：
2016-03-01 至 2016-10-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9035448
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 GNAS gene GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins General Population Genes Genotype Goals Hereditary Disease Home environment Hormonal Hormones Human Hypothalamic structure Impairment Inherited Institutes Investigation Lead Link Lymphocyte Metabolic Missense Mutation Mutation Names Neurocognitive Neurocognitive Deficit Neurodevelopmental Disorder Nonsense Mutation Obesity Patients Phenotype 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 growth hormone deficiency imprint mouse model paternal imprint psychosocial public health relevance sex sexual dimorphism 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.