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

Molecular Psychiatry volume 7, pages 1064–1074 (2002)Cite this article

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 (MAPT) 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 D17S1787 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.

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Acknowledgements

The authors are grateful to the family members for their kind cooperation in this study, and to Gerwin Roks and Hilda Kornman for the genealogy and ascertainment of family 1083. The authors also thank Thea Tadema for her technical advice with the PrP staining. This project was in part funded by the Fund for Scientific Research Flanders (FWO-F) and the International Research Foundation (IARF), Belgium; the Netherlands Organisation for Scientific Research (NWO), The Netherlands; and the Alzheimer Association, USA. MC is a postdoctoral fellow, and RR and BD are PhD fellows of the FWO-F.

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Authors and Affiliations

  1. Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UIA), Antwerpen, Belgium

    R Rademakers, M Cruts, B Dermaut, M Van den Broeck, H Backhovens, C M van Duijn & C Van Broeckhoven

  2. Department of Epidemiology & Biostatistics, Erasmus University Rotterdam, Rotterdam, The Netherlands

    K Sleegers & C M van Duijn

  3. Department of Neurology, University Hospital Rotterdam, Dijkzigt, Rotterdam, The Netherlands

    S M Rosso & J van Swieten

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Correspondence to C Van Broeckhoven.

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Rademakers, R., Cruts, M., Dermaut, B. et al. Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval. Mol Psychiatry 7, 1064–1074 (2002). https://doi.org/10.1038/sj.mp.4001198

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