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Journal Article

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


Bertram,  L.
Neuropsychiatric Genetics (Lars Bertram), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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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.

Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-F043-6
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.