title: Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region.
abstract: Familial frontotemporal dementia (FTD), characterized by tau-negative, ubiquitin-positive inclusions at autopsy, is linked to a chromosomal region at 17q21 (FTDU-17), encompassing the gene encoding the microtubule associated protein tau, MAPT. Mutations in MAPT were previously identified in familial FTD with parkinsonism (FTDP-17); however, in FTDU-17 patients, no pathogenic mutations were found in exonic regions consistent with the lack of tauopathy in FTDU-17 brains. Here, we excluded mutations in MAPT by genomic sequencing of 138.5 kb in FTDU-17 patients. Next, to facilitate the identification of the actual underlying genetic defect, we assembled the 6.5 Mb FTDU-17 sequence. Annotation demonstrated that MAPT is surrounded by three highly homologous low-copy repeats (LCRs) in a region of 1.7 Mb. Using evolutionary studies, short tandem repeat-based linkage disequilibrium (LD) and macro-restriction mapping, we demonstrated that these LCRs are at the basis of a series of rearrangements in the MAPT genomic region. One is an inversion that occurred 3 million years ago and resulted in a common polymorphism in humans to date. This inversion plus flanking LCRs spanned approximately 1.3 Mb and was shown to underlie the extended LD and haplotypes H1 and H2 across MAPT. However, in the FTDU-17 families, we ascertained segregation analysis precluding a relationship between the FTDU-17 and the H1/H2 inversion. The presence of multiple homologous LCRs in the region predicts that other potentially more complex genomic rearrangements might be underlying FTDU-17.
authors.affiliation: Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
authors.forename: Tim
authors.initials: T
authors.lastname: de Pooter
authors.forename: Peter
authors.initials: P
authors.lastname: de Rijk
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: Christine
authors.initials: C
authors.lastname: van Broeckhoven
mesh_terms: D007446:Chromosome Inversion / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D003704:Dementia / Q000235:genetics*; D019143:Evolution, Molecular; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D016875:tau Proteins
chemical_list: C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D016875:tau Proteins