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Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi182
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received April 14, 2005
Revised May 3, 2005
Accepted May 3, 2005

Article

Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low copy repeats in the tau region

Marc Cruts 1, Rosa Rademakers 1, Ilse Gijselinck 1, Julie van der Zee 1, Bart Dermaut 1, Tim De Pooter 1, Peter De Rijk 1, Jurgen Del-Favero 1, and Christine Van Broeckhoven 2*

1 Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium
2 Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp - Campus Drie Eiken, Universiteitsplein 1, B-2610 Antwerpen, Belgium

* To whom correspondence should be addressed.
Christine Van Broeckhoven, E-mail: christine.vanbroeckhoven{at}ua.ac.be


  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 3 highly homologous low-copy repeats (LCRs) in a region of 1.7 Mb. Using evolutionary studies, STR-based linkage disequilibrium 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 precluded 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.


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