Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

  title={Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17},
  author={Michael L. Hutton and Corinne L. Lendon and Patrizia Rizzu and Matt C. Baker and Susanne Froelich and Henry Houlden and Stuart Pickering-Brown and Sumi Chakraverty and Adrian M. Isaacs and Andrew Grover and Jennifer A. Hackett and Jennifer L. Adamson and Sarah J. Lincoln and Dennis W. Dickson and Peter Davies and Ronald C. Petersen and Martijn Stevens and Esther de Graaff and Erwin Wauters and J. van Baren and Marcel Hillebrand and Marijke Joosse and Jennifer M Kwon and Petra Nowotny and Li Che and Joanne B. Norton and John C. Morris and Lee A. Reed and John Q. Trojanowski and Hans Basun and Lars Lannfelt and Michael Neystat and Stanley Fahn and F. A. Dark and Tony Tannenberg and Peter R. Dodd and Nick Hayward and John B. J. Kwok and Peter R. Schofield and Athena Andreadis and Julie S. Snowden and David Craufurd and David Neary and Frank Owen and Ben A. Oostra and John Hardy and Alison M. Goate and John van Swieten and David M A Mann and Timothy Lynch and Peter Heutink},
Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics,. Previous studies have mapped the FTDP-17… 
Missense and splice site mutations in tau associated with FTDP-17: Multiple pathogenic mechanisms
The FTDP-17 missense and splice site mutations have multiple effects on the biology and function of tau and it is likely that these varied pathogenic mechanisms explain the wide range of clinical and neuropathologic features observed in the FT DP-17 tauopathies.
Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism.
Direct sequencing of the MAPT exonic sequences in 21 French FTDP families revealed in six index cases the same missense mutation in exon 10 resulting in a Pro301Leu change at amino acid 301, which might suggest that disruption of binding of MAPT protein to the microtubule is a key event in the pathogenesis of FTDP.
5′ Splice Site Mutations in tau Associated with the Inherited Dementia FTDP-17 Affect a Stem-Loop Structure That Regulates Alternative Splicing of Exon 10*
In vitro splicing assays and RNA structural analysis demonstrate that the mutations associated with fronto-temporal dementia and parkinsonism do indeed act through disruption of the stem-loop structure and that the stability of this secondary structure feature at least partially determines the ratio of tau exon 10+/− transcripts.
Phenotypic correlations in FTDP-17
Chromosome 17-linked Frontotemporal dementia with Ubiquitin-Positive, Tau-Negative Inclusions
The data suggest that FTD-U could represent an important subtype of FTD, and that identification of the underlying gene defect might significantly contribute to the understanding of the pathomechanism leading to neurodegeneration in this dementia subtype.
Search for a Mutation in the tau Gene in a Swiss Family with Frontotemporal Dementia
The main clinical and neuropathological features of a Swiss FTD family with members presenting a FTDP-like clinical phenotype are described and the existence of a yet unknown mechanism of neurodegeneration, other than via mutations near or within the microtubule-binding sites, or the exon 10 splice sites of the tau gene, has to be considered to explain dementia in this family.
Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
It is demonstrated that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis, and evidence that P GRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival is provided.
Extended investigation of tau and mutation screening of other candidate genes on chromosome 17q21 in a Swedish FTDP‐17 family
Further investigation of extended intron sequences or promoter regions of the tau gene and additional candidate genes on chromosome 17q21, therefore seems to be necessary in order to identify the additional causes of FTDP‐17.
The Tau N279K Exon 10 Splicing Mutation Recapitulates Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Tauopathy in a Mouse Model
It is demonstrated that transgenic mice expressing human tau protein with this mutation develop neurodegeneration as result of aberrant splicing, suggesting a possible mechanism for parkinsonism in FTDP-17.


Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21–22
This analysis included the microtubule‐associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease, and no pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.
Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21.
The genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements, and Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease.
Familial multiple-system tauopathy with presenile dementia is localized to chromosome 17.
Neuropathologic studies of nine affected individuals showed neuronal loss in several areas of the CNS, as well as argentophilic tau-immunopositive inclusions in neurons and in oligodendroglia.
Hereditary frontotemporal dementia is linked to chromosome 17q21—q22: A genetic and clinicopathological study of three dutch families
Evidence is reported for linkage to chromosome 17q21–q22 with a maximum lod score of 4.70 at Θ = 0.05, suggesting that a group of clinically related neurodegenerative disorders may originate from mutations in the same gene.
Localization of the gene for rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration to chromosome 17q21.
In this study, kindred evidence for linkage to chromosome 17q21 was obtained and the disease locus for a clinically distinct familial neurodegenerative disease named 'disinhibition-dementia-parkinsonism-amyotrophy complex' (DDPAC) was recently mapped to the same region of chromosome 17, suggesting that PPND and DDPAC may possibly originate from mutations in the same gene.
Linkage of frontotemporal dementia to chromosome 17: clinical and neuropathological characterization of phenotype.
A comparison of the clinical and pathological features in DUK1684 with those of the other chromosome 17-linked families, together with the linkage data, suggests that these families are allelic, emphasizing that genetic linkage analysis remains a useful tool for differentiating disease loci in clinically complex traits.
Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: A New Group of Tauopathies
The clinical and neuropathological features of the disease in these families suggest that Frontotemporal Dementia and Parkinsonism linked to chromosome 17 is a distinct disorder, with the presence of abundant tau deposits defining this disorder as a new tauopathy.
Autosomal dominant dementia with widespread neurofibrillary tangles
A Midwestern American pedigree spanning four generations in which 15 individuals were affected by early‐onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with α‐rich neurofibrillary pathology found in the brain post mortem is presented.
Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments.
A novel autosomal dominant disease named familial "multiple system tauopathy with presenile dementia," which is characterized by abundant fibrillary deposits of tau protein in both neurons and glial cells is described.
Frontotemporal dementia and parkinsonism linked to chromosome 17: A consensus conference
We held an international consensus conference on frontotemporal dementia, behavioral disturbances, and parkinsonism linked to chromosome 17 to determine whether these are homogeneous or heterogeneous