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The tau S305S mutation causes frontotemporal dementia with parkinsonism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular geriatric)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molecular geriatric)
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2008 (English)In: European Journal of Neurology, Vol. 15, no 2, 156-161 p.Article in journal (Refereed) Published
Abstract [en]

Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.

Place, publisher, year, edition, pages
2008. Vol. 15, no 2, 156-161 p.
Keyword [en]
frontotemporal dementia, FTDP-17, progressive supranuclear palsy, tau, tauopathy
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-98041DOI: 10.1111/j.1468-1331.2007.02017.xISI: 000252557200015PubMedID: 18093153OAI: oai:DiVA.org:uu-98041DiVA: diva2:173207
Available from: 2009-02-13 Created: 2009-02-13 Last updated: 2010-01-15Bibliographically approved
In thesis
1. Molecular Mechanisms of Frontotemporal Lobar Degeneration
Open this publication in new window or tab >>Molecular Mechanisms of Frontotemporal Lobar Degeneration
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases.

In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts.

Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency.

In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations.

In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2009. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 418
Keyword
Frontotemporal lobar degeneration, Frontotemporal dementia, Tau, Progranulin, Alternative splicing, Nonsense-mediated decay, Haploinsufficiency
Identifiers
urn:nbn:se:uu:diva-9550 (URN)978-91-554-7405-8 (ISBN)
Public defence
2009-03-06, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2009-02-13 Created: 2009-02-13Bibliographically approved

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