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).
The relevance to public health is that the project will enhance our understanding and provide new insights into mechanisms for chromosomal abnormalities that result from nonrecurrent rearrangements. Such genome rearrangements cause gene copy number changes that result in neurodevelopmental disorders such as mental retardation, behavioral disorders such as autism, and neurodegenerative disease such as Alzheimer's dementia.
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