UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis.
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.
Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia.
Kelly L
KL
Williams
Sadaf T
ST
Warraich
Shu
S
Yang
Jennifer A
JA
Solski
Ruvini
R
Fernando
Guy A
GA
Rouleau
Garth A
GA
Nicholson
Ian P
IP
Blair
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D034702:RNA-Binding Protein FUS / Q000235:genetics; D017422:Sequence Analysis, DNA; D013116:Spinal Cord / Q000473:pathology; D057177:TDP-43 Proteinopathies / Q000473:pathology; D014452:Ubiquitins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; C405662:UBQLN2 protein, human; D014452:Ubiquitins