Merner et al. (2012) reported a large multigenerational family with essential tremor. The age at onset was variable, ranging from the first to the fifth decade. Life expectancy was normal, and several patients over the average age of ... Merner et al. (2012) reported a large multigenerational family with essential tremor. The age at onset was variable, ranging from the first to the fifth decade. Life expectancy was normal, and several patients over the average age of ALS onset had no symptoms of that disease.
In affected members of a large family with hereditary essential tremor, Merner et al. (2012) identified a heterozygous mutation in the FUS gene (Q290X; 137070.0011). The mutation segregated with the disorder in all patients who were determined to ... In affected members of a large family with hereditary essential tremor, Merner et al. (2012) identified a heterozygous mutation in the FUS gene (Q290X; 137070.0011). The mutation segregated with the disorder in all patients who were determined to be 'definitely' or 'probably' affected. However, only 54% of those who were 'possibly' affected carried the mutation, and 1 unaffected individual who was 24 years old also carried the mutation. The mutation, which was found by exome sequencing, was demonstrated to result in nonsense-mediated mRNA decay. Sequencing the FUS gene in 270 probands with essential tremor found that 3 patients had 2 different heterozygous mutations (R216C, 137070.0007 and P431L, 137070.0012). Two of these patients had a family history of the disorder, but family members were not available for study. ETM4 patient lymphoblastoid cells with the FUS mutations showed significantly lower overall expression of mutant FUS mRNA compared to cells from patients with ALS6 due to FUS mutations. In addition, ETM4 cells with the mutations showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin, which was not seen with ALS6 FUS mutations. These findings indicated that truncating FUS mutations in ETM4 are associated with nonsense-mediated mRNA decay, whereas mutant FUS from ALS6 cells appear to escape nonsense-mediated mRNA decay. Thus, ETM4 may be due to loss of FUS function, whereas ALS6 may result from a toxic gain-of-function effect.