Identifying the Genetic and Molecular Basis of Clubfoot

确定马蹄内翻足的遗传和分子基础

基本信息

批准号：
8523936
负责人：
ANITA E BECK
金额：
$ 12.71万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523936
关键词：
18 year old Adult Affect Ankle Arthrogryposis Blood Vessels Characteristics Child Complex Congenital Abnormality Congenital clubfoot Contractile Proteins Contracture Development Diagnostic tests Disease Distal Economic Burden Environmental Risk Factor Etiology Gene Expression Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Risk Goals Hand Hereditary Disease Histology Inborn Genetic Diseases Individual Infant Inherited Knowledge Mechanics Mentors Molecular Molecular Genetics Morbidity - disease rate Motor Muscle Muscle Proteins Muscle function Musculoskeletal System Mutation Myosin Heavy Chains Neurologic Operative Surgical Procedures Pathogenesis Physical therapy Physicians Predisposition Principal Investigator Production Property Protein Isoforms Recombinant Proteins Reporting Research Personnel Research Technics Research Training Risk Risk Factors Scientist Severities Skeletal Muscle Syndrome Testing Translational Research Tropomyosin Troponin I Troponin T Universities Variant Washington base career foot genetic pedigree genetic risk factor improved in utero mutant novel novel diagnostics programs public health relevance reconstitution risk variant trait

项目摘要

DESCRIPTION (provided by applicant): Tlie overall goal of this project is to understand liow mutations in genes that encode contractile proteins cause clubfoot in a group of disorders called distal arthrogryposis (DA) syndromes and test whether variants in these genes influence risk for isolated clubfoot (IC). IC is a common birth defect affecting ~5,000 infants (about 1 in 735) born in the U.S. each year. One hypothesized cause of IC is abnormal muscle contractile forces acting in utero to malposition the ankle. However the mechanism by which contractile forces could be altered in the absence of an abnormal neurological exam is unclear. One strategy to discover this mechanism is to find polymorphisms that influence susceptibility to IC. IC is a complex trait that is influenced by several major genes, but to date no polymorphism has been strongly associated with IC risk. Clubfoot in neurologically normal individuals is the major characteristic of DAs. Recently, we have shown that DAs are caused by mutations in at least 7 genes (TNNI2, TNNT3, TPM2, MYH3, MYH8, l\/IYH2, MYH13) that encode contractile proteins expressed in skeletal muscle, and these mutations appear to alter the mechanical properties of reconstituted contractile complexes. We propose to 1) identify and characterize the genetic basis of two new dominantly-inherited DA disorders characterized by foot contractures and IC, 2) determine whether mutations in TNNI2, TNNT3, TPM2, and MYH3 alter the contractile properties of muscles in individuals with DA, and 3) test whether variants in genes that encode contractile proteins found in fast-twitch myofibers influence risk for IC. Identifying risk variants for IC and understanding the mechanism by which mutant contractile proteins affect muscle function will substantially improve our understanding of the pathogenesis of IC, facilitate the development of new diagnostic tests, and provide a basis for exploring novel therapies for IC. My goal is to develop a career as an independent physician-scientist devoted to utilizing translational research techniques to determine the molecular basis of genetic disorders in children. A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by a well-established investigator at the University of Washington. PUBLIC HEALTH RELEVANCE: Isolated clubfoot affects a total of ~100,000 U.S. children <18 years old. The goal of this project is to understand how mutations in genes that encode muscle proteins cause clubfoot in a group of contracture disorders called distal arthrogryposis and test whether variants in these genes influence risk for isolated clubfoot (IC). This knowledge will substantially improve our understanding of the pathogenesis of IC, facilitate the development of new diagnostic tests, and provide a basis for exploring novel therapies for IC.

描述（由申请人提供）：该项目的总体目标是了解编码收缩蛋白的基因中的LIOW突变引起俱乐部，这是一组称为远端关节炎（DA）综合症的疾病，并测试这些基因中的变体是否影响孤立的俱乐部杆的风险是否影响（我知道了）。 IC是每年在美国出生的约5,000名婴儿（约1分之一）的常见先天缺陷。 IC的一个假设原因是作用于子宫内的异常肌肉收缩力，导致踝关节不正确。但是，在没有异常神经系统检查的情况下，可以改变收缩力的机制尚不清楚。发现这种机制的一种策略是找到影响IC敏感性的多态性。 IC是一个复杂的特征，受几种主要基因影响，但迄今为止，没有多态性与IC风险密切相关。神经学上正常人的俱乐部是DA的主要特征。最近，我们表明DAS是由至少7个基因（TNNI2，TNNT3，TPM2，MYH3，MYH3，MYH8，L \/IYH2，MYH1，MYH13）引起的，它们编码在骨骼肌肉中表达的收缩蛋白，这些突变似乎会改变。重构收缩复合物的机械性能。我们建议1）识别和表征两种以脚签约和IC为特征的两种新的主要亲属DA疾病的遗传基础，2）确定TNNI2，TNNT3，TPM2和MYH3中的突变是否改变了患有DA患者肌肉的收缩特性，和3）测试在快速扭转肌纤维中发现的收缩蛋白的基因中的变体是否会影响IC的风险。确定IC的风险变异并了解突变体收缩蛋白影响肌肉功能的机制将大大改善我们对IC发病机理的理解，促进新的诊断测试的发展，并为探索IC的新疗法提供基础。我的目标是发展作为独立医师科学家的职业，致力于利用翻译研究技术来确定儿童遗传疾病的分子基础。提出了一项为期五年的指导计划，该计划将纳入教学培训和研究培训，并将在华盛顿大学的一位成熟的研究人员的指导下进行指导。公共卫生相关性：孤立的俱乐部脚步影响约100,000名美国儿童<18岁。该项目的目的是了解编码肌肉蛋白的基因中的突变如何引起一组称为远端关节炎远端关节炎的缔合障碍，并测试这些基因中的变体是否影响孤立的俱乐部（IC）的风险。这些知识将大大提高我们对IC发病机理的理解，促进新的诊断测试的发展，并为探索IC的新疗法提供基础。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Institutional protocol to manage consanguinity detected by genetic testing in pregnancy in a minor.

管理未成年人怀孕期间通过基因检测检测到的近亲关系的制度协议。

DOI：
10.1542/peds.2014-2593
发表时间：
2015
期刊：
Pediatrics
影响因子：
8
作者：
Chen,LauraP;Beck,AnitaE;Tsuchiya,KarenD;Chow,PennyM;Mirzaa,GhaydaM;Wiester,RebeccaT;Feldman,KennethW
通讯作者：
Feldman,KennethW

Single-nucleotide polymorphism arrays and unexpected consanguinity: considerations for clinicians when returning results to families.

单核苷酸多态性阵列和意外的血缘关系：临床医生将结果返回给家人时的考虑因素。

DOI：
10.1038/gim.2014.119
发表时间：
2015
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
0
作者：
Delgado,Fernanda;Tabor,HollyK;Chow,PennyM;Conta,JessieH;Feldman,KennethW;Tsuchiya,KarenD;Beck,AnitaE
通讯作者：
Beck,AnitaE