Nonrecurrent rearrangements, genome architecture and neurodegenerative disease.

非复发性重排、基因组结构和神经退行性疾病。

• 批准号: 7895924
• 负责人: JAMES R. LUPSKI
• 金额: $ 54.73万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895924
• 关键词: 17p; Address; Affect; Alzheimer' s Disease; Architecture; Autistic Disorder; Base Sequence; Behavior Disorders; Benign; Bioinformatics; Biological Assay; Chromosome abnormality; Chromosomes; Clinical; Code; Complex; Copy Number Polymorphism; DNA Sequence; DNA Sequence Rearrangement; Dementia; Diagnostic; Disease; Event; Gene Dosage; Genes; Genetic Recombination; Genome; Genomics; Homologous Gene; Inherited; Ligation; Maps; Mental Retardation; Microarray Analysis; Mutation; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neuropathy; Parents; Patients; Positioning Attribute; Predisposition; Public Health; Recombinants; Recurrence; Resolution; Sampling; Structure; Syndrome; Technology; Therapeutic; X Chromosome; autosome; clinical application; clinical phenotype; cohort; comparative genomic hybridization; insight; nervous system disorder; trait

It has become apparent during the last 15 years that many neurological disease traits are not the result of coding region mutations within genes, but instead manifest because of alterations of the genome. Diseases due to genomic rearrangements have been referred to as genomic disorders. In the post-genomic era, with widespread clinical application of high-resolution genome analyses by comparative genome hybridization (aCGH) and other array technologies, submicroscopic rearrangements are increasingly being recognized as a cause of neurologic disease. Genomic rearrangements can be recurrent with fixed positions for genomic breakpoints or nonrecurrent varying in size and with different breakpoints, but sharing a Smallest Region of Overlap (SRO) of a specific genomic interval among unrelated patients. We hypothesize that nonrecurrent rearrangements may occur by mechanisms that are distinct from well-established recombination mechanisms and our PRELIMINARY STUDIES strongly support this hypothesis. Furthermore, we suggest that some nonrecurrent rearrangements may result because of specific genomic architectural features causing susceptibility to such rearrangements. We will investigate these hypotheses experimentally by: 1) mapping breakpoints of duplication rearrangements, 2) bioinformatic analyses of the genomic region undergoing rearrangement, and 3) determining the products of recombination through direct DNA sequencing. Non recurrent duplication of 17p associated with Potocki-Lupski Syndrome (PTLS). and non recurrent PMP22 rearrangements associated with CMT1A or HNPP neuropathy will be studied in detail. In this manner we will identify the substrates for recombination, gain insights into genome architecture and regions involved, and potentially infer mechanism. Three specific aims are proposed: (1) Determine the sizes and breakpoint junctions of duplications of the proximal short arm of chromosome 17 associated with the Potocki-Lupski syndrome; (2) Carefully examine trios of patients with Potocki-Lupski syndrome who have nonrecurrent duplications to determine parent of origin, and structure of the parental chromosome on which the de novo duplication occurred; and (3) From a large cohort of patients with neuropathy who are screened for the recurrent CMT1A duplication and HNPP deletion by multiplex ligation- dependent probe amplification (MLPA) identify those that DO NOT have the usual recurrent CMT1A duplication or HNPP deletion and examine the structure of such nonrecurrent rearrangements by aCGH and determine the sequence at the breakpoint junctions. Our findings will have widespread diagnostic and therapeutic implications for these and other neurodegenerative diseases that can result from gene copy number variation (CNV).

在过去的15年里，很明显，许多神经系统疾病的特征并不是基因编码区突变的结果，而是由于基因组的改变而表现出来的。由基因组重排引起的疾病被称为基因组紊乱。在后基因组时代，通过比较基因组杂交（aCGH）和其他阵列技术进行高分辨率基因组分析的广泛临床应用，亚微观重排越来越被认为是神经系统疾病的一个原因。基因组重排可以在基因组断点的固定位置反复出现，也可以在大小和断点不同的情况下反复出现，但在无血缘关系的患者之间共享特定基因组间隔的最小重叠区域（SRO）。我们假设非复发性