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No evidence of PGRN or MAPT gene dosage alterations in a collection of patients with frontotemporal lobar degeneration
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molekylär geriatrik)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Molekylär geriatrik)
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2009 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 28, no 5, 471-475 p.Article in journal (Refereed) Published
Abstract [en]

Background/Aims

Alterations in gene dosage have recently been associated with neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, and deletions of the progranulin (PGRN) locus were recently described in patients with frontotemporal lobar degeneration (FTLD). FTLD is a genetically complex neurodegenerative disorder with mutations in the PGRN and the microtubule-associated protein tau (MAPT) genes being the most common known causes of familial FTLD. In this study, we investigated 39 patients with FTLD, previously found negative for mutations in PGRN and MAPT, for copy number alterations of these 2 genes.

Methods

Gene dosage analysis of PGRN and MAPT was performed using multiplex ligation-dependent probe amplification.

Results

We did not identify any PGRN or MAPT gene dosage variations in the 39 FTLD patients investigated.

Conclusion

We therefore conclude that alterations in gene copy number of PGRN and MAPT are not a cause of disease in this ollection of FTLD patients.

Place, publisher, year, edition, pages
2009. Vol. 28, no 5, 471-475 p.
Keyword [en]
Frontotemporal lobar degeneration, Frontotemporal dementia, Progranulin, Tau, Gene dosage alterations
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-98044DOI: 10.1159/000260046ISI: 000272607200012PubMedID: 19940479OAI: oai:DiVA.org:uu-98044DiVA: diva2:173210
Available from: 2009-02-13 Created: 2009-02-13 Last updated: 2011-10-06Bibliographically 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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Ingvast, SofieBrundin, RosemarieGiedraitis, VilmantasIngelsson, Martin

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