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Tau negative frontal lobe dementia at 17q21 : significant finemapping of the candidate region to a 4.8 cM interval

(2002) MOLECULAR PSYCHIATRY. 7(10). p.1064-1074
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Abstract
We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53-79 years). In this family we previously excluded the known Alzheimer's disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9-13 of the microtubule associated protein tau (MAP7) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D117S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5' regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.
Keywords
PERIPHERAL NERVOUS-SYSTEM, MOLECULAR-WEIGHT TAU, FAMILIAL ALZHEIMERS-DISEASE, PROGRESSIVE SUPRANUCLEAR PALSY, pair 17, human, chromosomes, mutation analysis, genetic linkage, genome-wide search, microtubule associated protein tau, dementia, frontotemporal lobar degeneration, FRONTOTEMPORAL DEMENTIA, PROTEIN-TAU, MISSENSE MUTATIONS, LATERAL-SCLEROSIS, LINKAGE ANALYSIS, GENE

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Citation

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Chicago
Rademakers, R, M Cruts, Bart Dermaut, K Sleegers, SM Rosso, M Van den Broeck, H Backhovens, J van Swieten, CM van Duijn, and C Van Broeckhoven. 2002. “Tau Negative Frontal Lobe Dementia at 17q21 : Significant Finemapping of the Candidate Region to a 4.8 cM Interval.” Molecular Psychiatry 7 (10): 1064–1074.
APA
Rademakers, R, Cruts, M., Dermaut, B., Sleegers, K., Rosso, S., Van den Broeck, M., Backhovens, H., et al. (2002). Tau negative frontal lobe dementia at 17q21 : significant finemapping of the candidate region to a 4.8 cM interval. MOLECULAR PSYCHIATRY, 7(10), 1064–1074.
Vancouver
1.
Rademakers R, Cruts M, Dermaut B, Sleegers K, Rosso S, Van den Broeck M, et al. Tau negative frontal lobe dementia at 17q21 : significant finemapping of the candidate region to a 4.8 cM interval. MOLECULAR PSYCHIATRY. 2002;7(10):1064–74.
MLA
Rademakers, R, M Cruts, Bart Dermaut, et al. “Tau Negative Frontal Lobe Dementia at 17q21 : Significant Finemapping of the Candidate Region to a 4.8 cM Interval.” MOLECULAR PSYCHIATRY 7.10 (2002): 1064–1074. Print.
@article{3200969,
  abstract     = {We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53-79 years). In this family we previously excluded the known Alzheimer's disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9-13 of the microtubule associated protein tau (MAP7) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D117S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5' regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.},
  author       = {Rademakers, R and Cruts, M and Dermaut, Bart and Sleegers, K and Rosso, SM and Van den Broeck, M and Backhovens, H and van Swieten, J and van Duijn, CM and Van Broeckhoven, C},
  issn         = {1359-4184},
  journal      = {MOLECULAR PSYCHIATRY},
  keywords     = {PERIPHERAL NERVOUS-SYSTEM,MOLECULAR-WEIGHT TAU,FAMILIAL ALZHEIMERS-DISEASE,PROGRESSIVE SUPRANUCLEAR PALSY,pair 17,human,chromosomes,mutation analysis,genetic linkage,genome-wide search,microtubule associated protein tau,dementia,frontotemporal lobar degeneration,FRONTOTEMPORAL DEMENTIA,PROTEIN-TAU,MISSENSE MUTATIONS,LATERAL-SCLEROSIS,LINKAGE ANALYSIS,GENE},
  language     = {eng},
  number       = {10},
  pages        = {1064--1074},
  title        = {Tau negative frontal lobe dementia at 17q21 : significant finemapping of the candidate region to a 4.8 cM interval},
  url          = {http://dx.doi.org/10.1038/sj.mp.4001198},
  volume       = {7},
  year         = {2002},
}

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