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Identification of a novel deletion in the splice donor site of progranulin exon 6
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
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Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-98043OAI: oai:DiVA.org:uu-98043DiVA: diva2:173209
Available from: 2009-02-13 Created: 2009-02-13 Last updated: 2010-01-13Bibliographically 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
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Available from: 2009-02-13 Created: 2009-02-13Bibliographically approved

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