Genetic and molecular pathophysiology of ATS

ATS 的遗传和分子病理生理学

基本信息

批准号：
9028719
负责人：
LOUIS J. PTACEK
金额：
$ 34.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028719
关键词：
Affect Arrhythmia Attention Binding Blood Blood specimen Characteristics Classification Clinical Code Collection Complex Consent DNA Data Dental Development Diagnosis Disease Distal Epilepsy Etiology Face Family Functional disorder Future Genes Genetic Genetic Models Glycogen Storage Disease Type IV Head Human Herpesvirus 4 In Vitro Individual Knowledge Lead Limb structure Link Membrane Migraine Molecular Genetics Molecular Profiling Mus Muscle Mutate Mutation Nature Neurocognitive Paralysed Pathway interactions Patients Phenotype Phosphatidylinositol 4,5-Diphosphate Physiological Physiology Potassium Channel Process Public Domains RNA Splicing Rare Diseases Reporting Sampling Syndrome Variant Work base cohort exome sequencing experience genetic pedigree insight lymphoblast meetings novel proband public health relevance therapeutic development

项目摘要

DESCRIPTION (provided by applicant) Andersen-Tawil Syndrome (ATS) is one of the familial periodic paralyses (FPP). It stands out among the other disorders in this group in that it is a multisystem disease. Andersen first reported a single case in 1971 that had episodic weakness, cardiac arrhythmias, and developmental features of the face, head, and distal limbs. Over the last two decades, we have characterized over 250 patients with ATS and laid down a detailed classification for these three aspects of this disorder (1-3). In addition, we have quantified the developmental phenotype and described additional features of the disorder including dental and neurocognitive phenotypes characteristic for this disorder (4, 5). We cloned a gene (KCNJ2) that is mutated in approximately 65% of all ATS families (6). The majority of the KCNJ2 mutations are believed to affect binding to PIP2 and close the potassium channel (7), but how this may cause the multisystem disease of ATS is still not clear. We've gone on to characterize the physiological consequences of patient-causing mutations in vitro and more recently generated a mouse carrying mutations of KCNJ2. The major thrust of the current proposal is to identify a second ATS gene and identify mutations causing ATS in the remaining unexplained patients. Identifying causal mutations in a second gene will greatly advance our understanding of the etiology of ATS. In addition, it may lead to better understanding of normal muscle physiology.

描述（由申请人提供） Andersen-Tawil综合征（ATS）是家庭周期性瘫痪（FPP）之一。它在该组的其他疾病中脱颖而出，因为它是一种多系统疾病。安德森（Andersen）在1971年首次报道了一个案例，其脸部，头部和远端的发育特征是情节性弱点，心律不齐和发育特征。在过去的二十年中，我们表征了250多名ATS患者，并针对该疾病的这三个方面进行了细节分类（1-3）。此外，我们已经量化了发育表型，并描述了该疾病的其他特征，包括该疾病的牙齿和神经认知表型（4、5）。我们克隆了一个基因（KCNJ2），该基因在大约65％的所有ATS家族中被突变（6）。据信，大多数KCNJ2突变会影响与PIP2的结合并关闭钾通道（7），但是这可能会导致ATS多系统疾病。我们继续表征体外引起患者突变的身体后果，最近产生了携带KCNJ2的小鼠突变。当前建议的主要目的是识别第二个ATS基因，并确定在其余意外患者中引起ATS的突变。在第二个基因中鉴定灾难性突变将大大提高我们对ATS病因的理解。此外，它可能会更好地了解正常的肌肉生理。