Comprehensive genomic approach to rare hearing disorders and ataxia

罕见听力障碍和共济失调的综合基因组方法

• 批准号: 7857691
• 负责人: Margit Burmeister
• 金额: $ 11.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7857691
• 关键词: Affect; Animal Model; Ataxia; Auditory; Bioinformatics; Biological Process; Candidate Disease Gene; Chromosome Mapping; Complementary DNA; Complex; DNA; Data; Databases; Diagnosis; Disease; Epilepsy; Exons; Familial disease; Family; Family Planning; Family Sizes; Foundations; Founder Effect; Future; Gene Chips; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genome; Genomics; Genotype; Goals; Grant; Haplotypes; Hearing problem; Heterogeneity; Individual; Intercept; Introns; Lead; Link; Linkage Disequilibrium; Literature; Location; Longitudinal Studies; Maps; Messenger RNA; Metabolic Pathway; Methods; Molecular; Mutate; Mutation; Neurofibromin 2; Neuropathy; Pathway interactions; Pattern; Process; Rare Diseases; Relative (related person); Research; Scientist; Signal Transduction; Stretching; Testing; Transcript; Transcriptional Regulation; Variant; case control; deafness; genetic analysis; genetic linkage; genetic linkage analysis; genetic variant; improved; lymphoblastoid cell line; member; mutant; neurotechnology; novel; positional cloning; public health relevance; research and development; response; tool

DESCRIPTION (provided by applicant): Positional cloning has helped identify the molecular causes of many of Mendelian disorders. Genes involved in the more common forms of deafness and ataxia have been identified and are often clinically tested. However, the cause of most genetically rare forms is still unknown because such families are often too small to provide by themselves sufficient statistical power to unambiguously identify linkage. In addition, even if families are large enough to identify a linked locus, the regions are typically so large that hundreds of genes are implicated. In some situations, linkage disequilibrium analysis can further narrow a region. Recently, global analysis of gene expression has become a reality. We hypothesize that a subset of mutated genes directly or indirectly leads to abnormal expression levels, and can be identified by combining genetic analysis with gene expression analysis of mRNA from lymphoblastoid cell lines (LCLs). Using such a combined approach, a novel epilepsy gene was recently identified in only three affected subjects. We have recently identified a novel auditory neuropathy gene, and have encouraging data for identification of a second novel deafness gene and for several novel ataxia genes. In this pilot/feasibility R21 grant, we will explore the generalizability of this approach in several families with unidentified causes of deafness or ataxia. We will perform genetic linkage, linkage disequilibrium and global gene expression analysis. Candidates genes will be identified as the intercept between genes in linkage regions and those that show significant expression changes. Computational approaches to define the intersect between genetic and gene expression data will be developed, implemented and tested. While in some cases combining genetic linkage and linkage disequilibrium with global gene expression analysis may directly identify the mutant gene, in other cases the mutation may result in functional differences in a pathway without affecting the expression of its own gene directly. In that case, more complex analysis of affected gene expression changes downstream of a mutant gene will be necessary to identify the deficient pathway and the mutation. Pathways from expression analysis, animal models and the literature and public bioinformatic databases will be used for this purpose. Candidate genes emerging from these approaches will be sequenced to identify variants, and potential mutations tested in unrelated controls. PUBLIC HEALTH RELEVANCE: The genetic cause of many forms of deafness or ataxia is still unknown. Our research will result in the identification of new genes and metabolic pathways involved in these disorders. These findings can improve accurate diagnosis, presymptomatic testing, family planning and personalizing treatment. It may also ultimately lead to new treatments.

描述（由申请人提供）：定位克隆有助于确定许多孟德尔疾病的分子原因。与更常见的耳聋和共济失调有关的基因已经被鉴定出来，并经常进行临床测试。然而，大多数遗传上罕见的形式的原因仍然是未知的，因为这些家庭往往太小，本身提供足够的统计能力，以明确地确定连锁。此外，即使家族足够大，可以识别出一个连锁基因座，但这些区域通常很大，涉及数百个基因。在某些情况下，连锁不平衡分析可以进一步缩小区域。最近，基因表达的全球分析已经成为现实。我们假设突变基因的子集直接或间接导致异常表达水平，并且可以通过将遗传分析与来自淋巴母细胞系（LCL）的mRNA的基因表达分析相结合来鉴定。使用这种组合方法，最近仅在三名受影响的受试者中发现了一种新的癫痫基因。我们最近发现了一个新的听神经病基因，并为确定第二个新的耳聋基因和几个新的共济失调基因提供了令人鼓舞的数据。在这个试点/可行性R21补助金，我们将探讨这种方法在几个家庭不明原因的耳聋或共济失调的普遍性。我们将进行遗传连锁，连锁不平衡和全球基因表达分析。候选基因将被鉴定为连锁区域中的基因与显示显著表达变化的基因之间的截距。将开发、实施和测试确定遗传和基因表达数据之间交叉点的计算方法。虽然在某些情况下，将遗传连锁和连锁不平衡与全局基因表达分析相结合可以直接鉴定突变基因，但在其他情况下，突变可能导致途径中的功能差异，而不直接影响其自身基因的表达。在这种情况下，需要对突变基因下游受影响的基因表达变化进行更复杂的分析，以确定缺陷途径和突变。来自表达分析、动物模型和文献以及公共生物信息学数据库的途径将用于此目的。从这些方法中出现的候选基因将被测序以识别变体，并在不相关的对照中测试潜在的突变。 公共卫生相关性：许多形式的耳聋或共济失调的遗传原因仍然未知。我们的研究将导致这些疾病中涉及的新基因和代谢途径的鉴定。这些发现可以提高准确的诊断，症状前测试，计划生育和个性化治疗。它也可能最终导致新的治疗方法。