Recent discoveries linking LINGO1, FUS and TENM4 to essential tremor have been met with cautious optimism since reproducibility and pathogenicity have been contentious in previously implicated genes.
Recently, a pathogenic FUS-Q290X mutation has been reported in a large ET-affected family; however, the pathophysiologic mechanism underlying FUS-linked ET is unknown.
Our findings provide no evidence for a role of rare genetic variants in the pathogenesis of ET, apart from the initially published FUS mutation segregating in a large ET family.
The entire coding sequence of FUS in 217 patients diagnosed with ET was analyzed and two missense variants in 219 healthy controls were genotyped by Sanger sequencing.
Recently, a mutation located in the nuclear export signal (NES) of the FUS gene has been reported to cause an autosomal dominant form of familial Essential tremor.
These findings and previous studies have shown that variants within the FUS gene are not a common cause of PD or ET, in comparison to their role in ALS.
Exome sequencing in a large essential tremor (ET) family identified a novel nonsense mutation (p.Q290X) in the fused in sarcoma gene (FUS) as the cause of this family.
Functional considerations suggest that the pathogenic effects of ET-specific FUS mutations are different from the effects observed when FUS is mutated in amyotrophic lateral sclerosis cases; we have shown that the ETFUS nonsense mutation is degraded by the nonsense-mediated-decay pathway, whereas amyotrophic lateral sclerosis FUS mutant transcripts are not.