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

作者：Gonzalez Perez Paloma; Lu Yubing; Chian Ru Ju; Sapp Peter C; Tanzi Rudolph E; Bertram Lars; McKenna Yasek Diane; Gao Fen Biao; Brown Robert H Jr^*

来源：Neurobiology of Disease, 2012, 48(3): 391-398.

DOI：10.1016/j.nbd.2012.06.018

• Amyotrophic lateral sclerosis
• Drosophila motor neuron disease
• TDP-43
• Ubiquilins

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.

• 出版日期2012-12