Analysis of tRNA Synthetase Variants in the Undiagnosed Diseases Program

未确诊疾病项目中 tRNA 合成酶变异体的分析

基本信息

批准号：
8915721
负责人：
Anthony Antonellis
金额：
$ 22.65万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915721
关键词：
Affect Alanine-tRNA Ligase Alleles Amino Acids Amino Acyl-tRNA Synthetases Aminoacylation Aspartate-tRNA Ligase Ataxia Binding Biochemical Biological Assay Biological Models Body Weight decreased Cardiomyopathies Cataloging Catalogs Catalytic Domain Cell Culture Techniques Cell Line Cells Communities Cultured Cells Cytoplasm DNA DNA Sequence Developmental Delay Disorders Disease Encephalopathies Enzymes Evaluation Failure to Thrive Family Family history of Family member Genes Genetic Genome Glycine-tRNA Ligase Health Hearing Hereditary Disease Human Human Genetics Impaired cognition In Vitro Individual Laboratories Link Microcephaly Molecular Mutation Nerve Degeneration Nuclear Onset of illness Ovarian Parents Pathogenicity Patients Peripheral Nervous System Diseases Phenotype Proteins Research Role Sampling Series Siblings Spastic Paraplegia Supporting Cell Technology Testing Therapeutic Toxic effect Transfer RNA Transfer RNA Aminoacylation Translations Variant Yeast Model System Yeasts Zebrafish base cell growth clinical phenotype clinically relevant cohort disease phenotype disease-causing mutation early onset gain of function genetic pedigree human disease human tissue improved in vivo insight loss of function next generation sequencing novel proband programs rare variant research clinical testing therapy development

项目摘要

DESCRIPTION (provided by applicant): Rapid advances in DNA sequencing technologies have allowed comprehensive analysis of patient samples for disease-associated mutations. A major complicating factor is that mutations are often found in small pedigrees or sporadic cases of disease making it difficult to build a strong genetic argument for pathogenicity. In these cases functional analyses are critical for evaluating the pathogenicity of rare variants. Furthermore, functional evaluation can provide insight into the molecular mechanism of disease as well as platforms for developing therapeutics. The Undiagnosed Diseases Program (UDP) is cataloging promising rare variants identified in patients with myriad clinical phenotypes. A subset of these variants reside in genes encoding aminoacyl-tRNA synthetases (ARSs), which are critical enzymes involved in charging tRNA with cognate amino acids. The UDP has identified six ARS variants-two each in glycyl-tRNA synthetase (GARS), alanyl-tRNA synthetase (AARS), and aspartyl-tRNA synthetase (DARS). Our laboratory specializes in evaluating the pathogenicity of ARS variants in vitro and in vivo. Indeed, we identified the first disease-associated ARS mutations in the GARS gene in 2003 and have been continuously studying this class of genes ever since. We propose two specific aims to evaluate the pathogenicity of the six ARS variants and to understand how they cause human genetic disease. First, we will test each ARS variant for a loss-of-function effect in biochemical, yeast complementation, and cellular localization assays. Second, we will determine if each ARS variant is able to exert a dominant, toxic phenotype in zebrafish, similar to other disease-associated ARS mutations. These efforts compose a thorough evaluation of the pathogenic potential of each ARS variant and will provide the basis for developing therapies for affected individuals.

描述（由申请人提供）：DNA测序技术的快速进步允许对患者样本进行疾病相关突变的全面分析。一个主要的复杂因素是，在小的血统书或零星的疾病病例中通常发现突变，因此很难为致病性建立强有力的遗传论点。在这些情况下，功能分析对于评估稀有变体的致病性至关重要。此外，功能评估可以提供有关疾病分子机制以及开发治疗剂平台的见解。未诊断的疾病计划（UDP）正在对无数临床表型患者中鉴定出的有希望的稀有变异分类。这些变体的一个子集存在于编码氨基酰基-TRNA合成酶（ARSS）的基因中，它们是与同源氨基酸一起为tRNA充电的关键酶。 UDP已经在糖基-TRNA合成酶（GARS），丙型烷基tRNA合成酶（AARS）和Aspartyl-tRNA合成酶（DARS）中鉴定了六个ARS变体。我们的实验室专门评估体外和体内ARS变体的致病性。确实，我们在2003年确定了GARS基因中第一个与疾病相关的AR突变，此后一直在不断研究这类基因。我们提出了两个特定的目的，以评估六种AR变体的致病性，并了解它们如何引起人类遗传疾病。首先，我们将测试每个ARS变体，以在生化，酵母互补和细胞定位测定中产生功能丧失效应。其次，我们将确定每个ARS变体是否能够在斑马鱼中发挥优势，有毒的表型，类似于其他与疾病相关的ARS突变。这些努力对每种ARS变体的致病潜力进行了彻底的评估，并将为受影响个体开发疗法提供基础。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease.

DOI：
10.1016/j.ejmg.2018.04.005
发表时间：
2018-10
期刊：
European journal of medical genetics
影响因子：
1.9
作者：
Rips J;Meyer-Schuman R;Breuer O;Tsabari R;Shaag A;Revel-Vilk S;Reif S;Elpeleg O;Antonellis A;Harel T
通讯作者：
Harel T

Bi-allelic IARS mutations in a child with intra-uterine growth retardation, neonatal cholestasis, and mild developmental delay.

DOI：
10.1111/cge.12930
发表时间：
2017-06
期刊：
Clinical genetics
影响因子：
3.5
作者：
Orenstein N;Weiss K;Oprescu SN;Shapira R;Kidron D;Vanagaite-Basel L;Antonellis A;Muenke M
通讯作者：
Muenke M

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations.

DOI：
10.1016/j.ymeth.2016.11.013
发表时间：
2017-01-15
期刊：
Methods (San Diego, Calif.)
影响因子：
0
作者：
Oprescu SN;Griffin LB;Beg AA;Antonellis A
通讯作者：
Antonellis A

Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation.

DOI：
10.1002/humu.23287
发表时间：
2017-10
期刊：
Human mutation
影响因子：
3.9
作者：
Oprescu SN;Chepa-Lotrea X;Takase R;Golas G;Markello TC;Adams DR;Toro C;Gropman AL;Hou YM;Malicdan MCV;Gahl WA;Tifft CJ;Antonellis A
通讯作者：
Antonellis A