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

(2005) HUMAN MOLECULAR GENETICS. 14(13). p.1753-1762
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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 similar to 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.
Keywords
EVOLUTION, PROGRESSIVE SUPRANUCLEAR PALSY, REARRANGEMENTS, RECOMBINATION, HAPLOTYPE, DISEASE, GENE, TAUOPATHIES, DISORDERS, MUTATIONS

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Chicago
Cruts, Marc, Rosa Rademakers, Ilse Gijselinck, Julie van der Zee, Bart Dermaut, Tim de Pooter, Peter de Rijk, Jurgen Del-Favero, and Christine van Broeckhoven. 2005. “Genomic Architecture of Human 17q21 Linked to Frontotemporal Dementia Uncovers a Highly Homologous Family of Low-copy Repeats in the Tau Region.” Human Molecular Genetics 14 (13): 1753–1762.
APA
Cruts, Marc, Rademakers, R., Gijselinck, I., van der Zee, J., Dermaut, B., de Pooter, T., de Rijk, P., et al. (2005). Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. HUMAN MOLECULAR GENETICS, 14(13), 1753–1762.
Vancouver
1.
Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, de Pooter T, et al. Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. HUMAN MOLECULAR GENETICS. 2005;14(13):1753–62.
MLA
Cruts, Marc, Rosa Rademakers, Ilse Gijselinck, et al. “Genomic Architecture of Human 17q21 Linked to Frontotemporal Dementia Uncovers a Highly Homologous Family of Low-copy Repeats in the Tau Region.” HUMAN MOLECULAR GENETICS 14.13 (2005): 1753–1762. Print.
@article{3200604,
  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 similar to 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.},
  author       = {Cruts, Marc and Rademakers, Rosa and Gijselinck, Ilse and van der Zee, Julie and Dermaut, Bart and de Pooter, Tim and de Rijk, Peter and Del-Favero, Jurgen and van Broeckhoven, Christine},
  issn         = {0964-6906},
  journal      = {HUMAN MOLECULAR GENETICS},
  keywords     = {EVOLUTION,PROGRESSIVE SUPRANUCLEAR PALSY,REARRANGEMENTS,RECOMBINATION,HAPLOTYPE,DISEASE,GENE,TAUOPATHIES,DISORDERS,MUTATIONS},
  language     = {eng},
  number       = {13},
  pages        = {1753--1762},
  title        = {Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region},
  url          = {http://dx.doi.org/10.1093/hmg/ddi182},
  volume       = {14},
  year         = {2005},
}

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