Properties and determinants of GAA repeat instability

GAA 重复不稳定性的特性和决定因素

基本信息

批准号：
7162502
负责人：
SANJAY I BIDICHANDANI
金额：
$ 25.59万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7162502
关键词：
Abbreviations Abnormal coordination Affect Alleles Ataxia Autopsy Base Sequence Biological Models Blood Brain Stem COS Cells Cardiomyopathies Cerebellum Cerebrum Chromosomes Contracts CpG Islands DNA DNA biosynthesis Data Development Diabetes Mellitus Disease Epigenetic Process Exhibits Fibroblasts Fragile X Syndrome Friedreich Ataxia Future Generations Genes Genetic Genetic Polymorphism Genetic Transcription Genome Germ Germ Cells Goals Guanine + Cytosine Composition Heart Hela Cells Human Human Genome Huntington Disease In Vitro Individual Inherited Introns Lead Length Leukocytes Location Methylation Mitotic Modification Molecular Muscle Mutation Myotonic Dystrophy Neurons Nuclear Extract Oral mucous membrane structure Pancreas Patients Pattern Peripheral Plasmids Polymerase Chain Reaction Process Property Range Replication Origin Research Personnel Role SV40 T Antigens Simian virus 40 Skin Somatic Cell Spinal Cord Spinal Ganglia Staging System Techniques Testing Time Tissues Trinucleotide Repeats Triplet Multiple Birth Variant base bisulfite cell type frataxin genetic analysis genome sequencing in vivo insight intergenerational lymphoblast lymphoblastoid cell line mutant nervous system disorder novel strategies prevent programs research study sciatic nerve size sperm cell sural transmission process

项目摘要

DESCRIPTION (provided by applicant): Friedreich ataxia is an autosomal recessive disease, characterized clinically by ataxia (incoordination), cardiomyopathy and diabetes. The most common mutation, seen in >95% of patients is an abnormal expansion of a GAA triplet-repeat sequence in intron 1 of the FRDA (frataxin) gene. Normal and mutant alleles contain 6 - 100 and 100 - 1700 triplets, respectively. Expanded (mutant) alleles exhibit marked instability in somatic cells and during intergenerational transmission. Disease-causing expansions arise when premutation alleles (30 - 100 triplets) undergo hyperexpansion during intergenerational transmission. The mechanism of hyperexpansion of premutation alleles and the subsequent somatic and germline instability of expanded alleles remains poorly understood. The overall goal of this project is to investigate the mutagenic mechanisms underlying the genetic instability of the GAA triplet-repeat sequence. We will perform "small-pool PCR" (SP-PCR) analysis to test the pattern of genetic instability of normal, premutation, and expanded chromosomes, in a wide variety of somatic tissues and germ cells derived from patients and asymptomatic carriers of various alleles. We will investigate the effect of DNA replication on GAA triplet-repeat instability using a defined eukaryotic replication model system. We will also investigate the role of cis-acting and epigenetic modifiers in determining instability of the GAA triplet-repeat sequence. It is hoped that these studies will lead to the development of novel strategies to prevent or reverse the process of GAA triplet-repeat expansion as a possible future therapy for Friedreich ataxia. Our data could potentially lead to the discovery of general properties of triplet-repeat instability, which will have implications for other diseases caused by this mutational mechanism.

描述（由申请人提供）：Friedreich 共济失调是一种常染色体隐性遗传疾病，临床特征为共济失调（不协调）、心肌病和糖尿病。最常见的突变（>95% 的患者）是 FRDA（frataxin）基因内含子 1 中 GAA 三联体重复序列的异常扩增。正常和突变等位基因分别包含 6 - 100 和 100 - 1700 个三联体。扩展的（突变）等位基因在体细胞和代际传播过程中表现出明显的不稳定。当前突变等位基因（30 - 100 个三联体）在代际传播过程中经历过度扩张时，就会出现引起疾病的扩张。前突变等位基因的过度扩增以及随后扩增的等位基因的体细胞和种系不稳定的机制仍然知之甚少。该项目的总体目标是研究 GAA 三联体重复序列遗传不稳定性背后的诱变机制。我们将进行“小池 PCR”(SP-PCR) 分析，以测试来自患者和各种等位基因无症状携带者的各种体细胞组织和生殖细胞中正常、前突变和扩增染色体的遗传不稳定性模式。我们将使用定义的真核复制模型系统研究 DNA 复制对 GAA 三联体重复不稳定性的影响。我们还将研究顺式作用和表观遗传修饰剂在确定 GAA 三联体重复序列的不稳定性中的作用。希望这些研究将导致开发新策略来预防或逆转 GAA 三联体重复扩增过程，作为未来可能治疗 Friedreich 共济失调的方法。我们的数据可能会导致三联体重复不稳定性的一般特性的发现，这将对由这种突变机制引起的其他疾病产生影响。