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

Neurobiol Dis. 2012 Dec;48(3):391-8. doi: 10.1016/j.nbd.2012.06.018. Epub 2012 Jul 3.


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 UBQLN1E54D 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amyotrophic Lateral Sclerosis / genetics*
  • Autophagy-Related Proteins
  • Blotting, Western
  • Bulbar Palsy, Progressive / genetics*
  • Carrier Proteins / genetics*
  • Cell Cycle Proteins / genetics*
  • DNA Mutational Analysis
  • Female
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Male
  • Mutation
  • Polymorphism, Single Nucleotide
  • Transfection


  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • UBQLN1 protein, human

Supplementary concepts

  • Brown-Vialetto-Van Laere syndrome