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キーワード:
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
要旨:
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.
