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  Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS

Gonzalez-Perez, P., Lu, Y. B., Chian, R. J., Sapp, P. C., Tanzi, R. E., Bertram, L., et al. (2012). Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS. Neurobiology of Disease, 48(3), 391-398. doi:DOI 10.1016/j.nbd.2012.06.018.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F043-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F044-4
Genre: Journal Article

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 Creators:
Gonzalez-Perez, P., Author
Lu, Y. B., Author
Chian, R. J., Author
Sapp, P. C., Author
Tanzi, R. E., Author
Bertram, L.1, Author              
McKenna-Yasek, D., Author
Gao, F. B., Author
Brown, R. H., Author
Affiliations:
1Neuropsychiatric Genetics (Lars Bertram), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479655              

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Free keywords: amyotrophic lateral sclerosis drosophila motor neuron disease tdp-43 ubiquilins amyotrophic-lateral-sclerosis amyloid precursor protein alzheimers-disease hexanucleotide repeat ubiquilin interacts gene tdp-43 onset family fus
 Abstract: Genetic variants in UBQLN1 gene have been linked to neurodegeneration and mutations in UBQLN2 have recently been identified as a rare cause of amyotrophic lateral sclerosis (ALS). Objective: To test if genetic variants in UBQLN1 are involved in ALS. Methods: 102 and 94 unrelated patients with familial and sporadic forms of ALS were screened for UBQLN1 gene mutations. Single nucleotide variants were further screened in a larger set of sporadic ALS (SALS) patients and unrelated control subjects using high-throughput Taqman genotyping; variants were further assessed for novelty using the 1000Genomes and NHLBI databases. In vitro studies tested the effect of UBQLN1 variants on the ubiquitin-proteasome system (UPS). Results: Only two UBQLN1 coding variants were detected in the familial and sporadic ALS DNA set; one, the missense mutation p.E54D, was identified in a single patient with atypical motor neuron disease consistent with Brown-Vialetto-Van Laere syndrome (BVVLS), for whom c20orf54 mutations had been excluded. Functional studies revealed that UBQLN1(E54D) protein forms cytosolic aggregates that contain mislocalized TDP-43 and impairs degradation of ubiquitinated proteins through the proteasome. Conclusions: Genetic variants in UBQLN1 are not commonly associated with ALS. A novel UBQLN I mutation (E45D) detected in a patient with BVVLS altered nuclear TDP-43 localization in vitro, suggesting that UPS dysfunction may also underlie the pathogenesis of this condition. (c) 2012 Elsevier Inc. All rights reserved.

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Language(s): eng - English
 Dates: 2012-07-032012-12
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: DOI 10.1016/j.nbd.2012.06.018
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Title: Neurobiology of Disease
  Other : Neurobiol. Dis.
Source Genre: Journal
 Creator(s):
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Publ. Info: Oxford : Academic Press
Pages: - Volume / Issue: 48 (3) Sequence Number: - Start / End Page: 391 - 398 Identifier: ISSN: 0969-9961
CoNE: /journals/resource/954922649144