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Title
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Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration
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Author
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Abstract
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| Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08-1.88, P = 0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P = 0.022), the USA (OR 1.4 95% CI 1.02-1.92, P = 0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97-2.17, P = 0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72-1.37, P = 0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43. (C) 2009 Elsevier Inc. All rights reserved. |
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Language
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English
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Source (journal)
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Neurobiology of aging. - Fayetteville, N.Y.
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Publication
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Fayetteville, N.Y.
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2009
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ISSN
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0197-4580
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DOI
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10.1016/J.NEUROBIOLAGING.2009.01.009
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Volume/pages
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30
:4
(2009)
, p. 656-665
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ISI
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000264579500021
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Full text (Publisher's DOI)
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