P3–152: Direct evidence for a large inversion of the MAPT genomic region using fish of mechanically stretched chromosomes
Year: 2006
Type: article
Abstract: Ubiquitin–positive tau–negative frontotemporal dementia is localized to a region at chromosome 17q21 (FTDU–17) including the microtubule associated protein tau gene (MAPT). Although MAPT is the most obvious positional candidate gene, extensive mutation screening studies failed to identify a MAPT mutation in FTDU–17 patients. We have previously demonstrated that the MAPT genomic region is genetically and genomically complex due to a novel family of highly homologous MAPT low–copy repeats (LCRs) of which three are located in the FTDU–17 locus: LCR A, LCR B and LCR C. We have previously demonstrated that a region of 1.3 Mb with complete linkage disequilibrium (LD) resulting in the two major MAPT haplotypes, H1 and H2, coincided with the region enclosed by inverted repeats LCR A and LCR B. The lack of recombination between H1 and H2 can be explained by an ancient paracentric inversion, most likely due to a non–allelic homologous recombination event involving LCR A and LCR B. The aim of this study was to prove this inversion using a direct detection method. Due to the intermediate size of the inversion, classical fluorescence in situ hybridization (FISH) methods including metaphase, interphase and fiber–FISH failed to demonstrate the inversion. Therefore, we performed FISH experiments with mechanically stretched metaphase chromosomes reaching a unique intermediate resolution. In contrast to previous studies suggesting the H1–H2 inversion polymorphism using indirect methods, this study unambiguously showed for the first time the large H1–H2 inversion due to the optimal resolution of this FISH technique. Since we have established now the instability of the MAPT LCRs and several inversion polymorphisms have been identified in association with genomic disorders, we hypothesize that these LCRs could give rise to other more complex genomic rearrangements of the MAPT region, possibly involved in the molecular pathogenesis of FTDU–17 and other related tauopathies. Current research aims at the identification of such reorganizations.
Source: Alzheimer s & Dementia
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W3021971141