Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS
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Authors
Gonzalez-Perez, PalomaLu, Yubing
Chian, Ru-ju
Sapp, Peter
Tanzi, Rudolph E.
Bertram, Lars
McKenna-Yasek, Diane
Gao, Fen-Biao
Brown, Robert H. Jr.
UMass Chan Affiliations
Department of NeurologyDocument Type
Journal ArticlePublication Date
2012-07-03Keywords
Amyotrophic Lateral SclerosisCarrier Proteins
Cell Cycle Proteins
Nervous System Diseases
Neurology
Neuroscience and Neurobiology
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Show full item recordAbstract
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 UBQLN1 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.Source
Neurobiol Dis. 2012 Jul 3;48(3):391-398. [Epub ahead of print] Link to article on publisher's siteDOI
10.1016/j.nbd.2012.06.018Permanent Link to this Item
http://hdl.handle.net/20.500.14038/37742PubMed ID
22766032Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.nbd.2012.06.018