UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis

作者：Williams Kelly L; Warraich Sadaf T; Yang Shu; Solski Jennifer A; Fernando Ruvini; Rouleau Guy A; Nicholson Garth A; Blair Ian P^*

来源：Neurobiology of Aging, 2012, 33(10): 2527.e3.

DOI：10.1016/j.neurobiolaging.2012.05.008

• Amyotrophic lateral sclerosis
• Exome sequencing
• Mutation
• UBQLN2
• Ubiquilin 2

Amyotrophic lateral sclerosis (ALS) shows clinical and pathological overlap with frontotemporal dementia that includes the presence of hallmark ubiquitinated inclusions in affected neurons. Mutations in UBQLN2, which encodes ubiquilin 2, were recently identified in X-linked juvenile and adult-onset ALS and ALS/dementia. As part of an established exome sequencing program to identify disease genes in familial ALS, we identified a novel missense UBQLN2 mutation (c. 1460C>T, p. T487I) in 2 apparently unrelated multigenerational ALS families with no evidence of frontotemporal dementia. This mutation segregated with the disease and was absent in 820 healthy controls and all public single nucleotide polymorphism databases. The UBQLN2 p. T487I mutation substitutes a highly conserved residue and is located immediately upstream of a PXX region where all previous mutations have been identified. Immunostaining of spinal cord from a patient with UBQLN2 p. T487I mutation showed colocalization of ubiquilin 2 with ubiquitin in all neuronal inclusions examined and frequent colocalization with TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma protein (FUS). To examine ubiquilin 2 pathology in broader ALS, we showed that ubiquilin 2 pathology also extends to ALS with a FUS mutation. These data further support the importance of ubiquilin 2 in the pathogenesis of ALS.

• 出版日期2012-10