Identifying genetic factors that cause and modify CMT

识别导致和改变 CMT 的遗传因素

• 批准号: 8918127
• 负责人: Stephan Zuchner
• 金额: $ 29.65万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918127
• 关键词: Accounting; Amyotrophic Lateral Sclerosis; Area; Candidate Disease Gene; Clinical Research; Clinical Trials; Code; Communities; Counseling; Data; Databases; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Family; Functional RNA; Funding Agency; Gene-Modified; Genes; Genetic; Genome; Genomics; Goals; Individual; Inherited; Interest Group; International; Intervention; Knowledge; Link; Multiple Sclerosis; Mutation; Natural History; Neuropathy; Outcome; Pathogenesis; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenotype; Physicians; Price; Rare Diseases; Research; Research Personnel; Research Project Grants; Resources; Sample Size; Sampling; Secure; Sequence Analysis; System; Systems Analysis; Time; Variant; Vertebral column; Work; axonal degeneration; base; early onset; exome; feeding; genetic risk factor; genome analysis; genome wide association study; genome-wide; hereditary neuropathy; member; new technology; next generation sequencing; novel; tool

More than 70 different genes have been identified to cause the various forms of CMT. For the demyelinating forms of CMT, a genetic cause can be found most of the time, with CMT1A (PMP22 duplication) explaining ~70% of these cases. In contrast, a mutation in one of the currently known genes can be found in less than 40% of axonal (CMT2) cases, mostly for the severe, early onset cases. Genetic studies have fundamentally transformed our knowledge on CMT and have catalyzed much of the research in neuropathies in the past 20 years. We fully expect that by taking advantage of new technologies, this progress will continue to a point where (1) >90% of CMT1 and CMT2 patients can receive a genetic diagnosis; (2) a sizable number of important genetic modifiers that account for a significant portion of the phenotypic variability in some forms of CMT will be identified; (3) a proportion of the heretofore idiopathic/sporadic neuropathies will be found to have a genetic cause; (4) genetic risk factors for developing neuropathy to diabetes and various medications will be identified. The members of the INC consortium work in a collaborative manner with multiple sources of funding to achieve these goals. In particular, the INC has allowed us to collect high-quality samples for reliable gene modifier studies, as demonstrated by our results on a CMT1A study. In this renewal, we propose to expand our efforts to find new genes that cause CMT and genetic modifiers of CMT. These modifiers will be important targets for intervention, and may well be important in the manifestations of acquired peripheral neuropathies, and even other diseases, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis, in which axonal degeneration has been implicated in the pathogenesis. Finally, as our collaborative group and others move rapidly towards genomic approaches, we will establish a unified, secure, and accessible resource for all genomic data of the INC that will be open to all CMT researchers, that can also serve as a blueprint for other RDCRN groups interested in inherited diseases.

已经确定了70多种不同的基因导致各种形式的CMT。对于CMT的脱髓鞘形式，大多数情况下可以找到遗传原因，其中CMT 1A（PMP 22重复）解释了约70%的病例。相比之下，目前已知的基因之一的突变可以在不到40%的轴突（CMT 2）病例中发现，大多数是严重的早发性病例。遗传学研究从根本上改变了我们对CMT的认识，并在过去20年中催化了许多神经病的研究。我们完全期望通过利用新技术，这一进展将继续到以下程度：（1）>90%的CMT 1和CMT 2患者可以接受基因诊断;（2）相当数量的重要遗传修饰剂将被鉴定，这些修饰剂在某些形式的CMT中占表型变异的显著部分;（3）迄今为止的特发性/散发性神经病的一部分将被发现具有遗传原因;（4）将鉴定发展为糖尿病和各种药物的神经病的遗传危险因素。 INC财团的成员以合作的方式与多种资金来源合作，以实现这些目标。特别是，INC使我们能够收集高质量的样本进行可靠的基因修饰剂研究，正如我们在CMT 1A研究中的结果所证明的那样。在这次更新中，我们建议扩大我们的努力，以找到新的基因，导致CMT和遗传修饰剂的CMT。这些修饰剂将是重要的干预目标，并且在获得性周围神经病的表现中很可能是重要的，甚至在发病机制中涉及轴突变性的其他疾病，如肌萎缩性侧索硬化症（ALS）和多发性硬化症中也是重要的。最后，随着我们的合作小组和其他人迅速走向基因组方法，我们将为INC的所有基因组数据建立一个统一，安全和可访问的资源，该资源将向所有CMT研究人员开放，这也可以作为对遗传性疾病感兴趣的其他RDCRN小组的蓝图。