Phenotype and Genotype of Autosomal Dominant Alzheimer's Disease in Jalisco, Mexico

墨西哥哈利斯科州常染色体显性阿尔茨海默病的表型和基因型

基本信息

批准号：
10668453
负责人：
JOHN M RINGMAN
金额：
$ 63.16万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668453
关键词：
Adult Advocacy Affect Age Age of Onset Alzheimer&apos s Disease Amyloid Beta A4 Precursor Protein C9ORF72 CSF1R gene California Clinic Clinical Clinical Research Clinical Trials Clinical assessments Cognitive Collaborations Colombia Data Set Development Disease Elements Ethics Evaluation Extended Family Family Founder Effect Functional disorder Funding Future Gender Genes Genetic Genetic Counseling Genetic Predisposition to Disease Genetic Screening Genetic study Genotype Goals Impaired cognition Infrastructure International Intervention Leg Measures Medical Genetics Mentorship Mexican Mexico Mutation Neurodegenerative Disorders Neurologic Neuropsychology Onset of illness Pathogenicity Patient Care Performance Persons Phase Phenotype Population Populations at Risk PrP gene Prevention Procedures Protocols documentation Reporting Research Research Infrastructure Research Personnel Resources Risk Spastic Paraparesis Standardization System Technology Testing Training United States National Institutes of Health Universities Work autosomal dominant Alzheimer&apos s disease autosome behavioral phenotyping cognitive testing cohort disease phenotype disease-causing mutation evidence base exome sequencing familial Alzheimer disease genetic testing genetic variant improved mutation carrier presenilin-1 presenilin-2 presymptomatic testing prospective research clinical testing research study standardize measure

项目摘要

The study of persons with or at-risk for genetically-determined autosomal dominant Alzheimer’s disease (ADAD) due to mutations in the PSEN and APP genes has made tremendous contributions to our understanding of AD in general. As the future development of AD in persons inheriting ADAD mutations can be reliably predicted, one can define the disease phenotype and changes occurring during the presymptomatic phase of the disease with great sensitivity, enabling the evaluation of other factors influencing disease course (e.g. modifying genes, effects of putative disease-modifying interventions). Such research is facilitated by the identification of large families sharing the same genetic predisposition, an approach that has been best implemented in an extended family in Colombia with a common mutation in PSEN1 (E280A). A similar founder effect for a distinct mutation in PSEN1 (A431E) and another large family with a different ADAD-causing mutation in APP (V717I) has been identified in the State of Jalisco in Mexico but to date these families have been understudied. The goal of the current application is to facilitate the performance of clinical studies of this population by investigators in Jalisco. This will be achieved through the following specific aims: Specific Aim #1) To characterize and follow persons with and at-risk for ADAD in Jalisco by harmonizing measures between the Centro de Investigación Biomédica de Occidente Genetics clinic in Guadalajara, the University of Guadalajara Polyclinic in Tepatitlan, and the USC Alzheimer’s Disease Research Center. By providing gene-sequencing technology and training, we will also enable the genetic characterization of this population. Specific Aim #2) To perform studies to identify genes that affect the age of disease onset and the presence of leg stiffness in ADAD. Specific Aim #3) To improve the ability of clinicians and researchers in Jalisco to deliver presymptomatic genetic counseling for persons at-risk for ADAD, thus optimizing autonomy with regards to research participation. This project will improve our understanding of the pathophysiology of ADAD and lay the groundwork for future studies of this informative population in Mexico.

对遗传确定的常染色体显性阿尔茨海默氏症患者的研究由于PSEN和APP基因的突变引起的疾病（ADAD）为我们对广告的理解总体上。作为继承ADAD的人的未来广告的发展可以可靠地预测突变，可以确定疾病表型和发生变化在疾病的抑制阶段，具有很高的敏感性，从而评估其他影响疾病病程的因素（例如修改基因，推定疾病改良的影响干预措施）。通过识别大型家庭共享相同的研究，准备了此类研究遗传易感性，一种在哥伦比亚大家庭中最好实施的方法在PSEN1（E280A）中具有共同的突变。 PSEN1中明显突变的类似创始人效应（A431E）和另一个在APP（v717i）中具有不同ADAD引起突变的大家庭已有在墨西哥的哈利斯科州被确定，但迄今已了解了这些家庭。目标当前的应用是通过哈利斯科州的调查人员。这将通过以下特定目的实现：具体目标＃1）表征并跟随和关注Adad在Jalisco的Adad的人。在Centro de Resjuction contovernBioMédicade coccente遗传诊所之间的协调测量瓜达拉哈拉（Guadalajara），瓜达拉哈拉大学（Guadalajara）多克林（Tepatitlan）和南加州大学阿尔茨海默氏病研究中心。通过提供基因测序技术和培训，我们还将启用该人群的遗传特征。具体目的＃2）进行研究以鉴定影响疾病开始时代和 ADAD的腿部刚度。特定目的＃3）提高了哈利斯科州临床医生和研究人员提供交付的能力为ADAD危险的人们的遗传咨询，从而优化自主权考虑研究参与。该项目将提高我们对ADAD的病理生理学的理解，并放置墨西哥这个信息人群的未来研究的基础。