Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia

Abstract

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE).

Methods: All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561-726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations.

Results: We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations.

Conclusions: FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and approximately 4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.

Figure 1 Cosegregation of FUS mutations in representative familial amyotrophic lateral sclerosis pedigrees Affected patients are marked by a black symbol, unaffected with an open symbol. A slashed symbol indicates a deceased patient. + = With the mutation; − = without the mutation; (+) = genotype inferred. Gender and birth order have been omitted for reasons of confidentiality.

Figure 2 Comparison of age at symptom onset Kaplan-Meier analysis. Y-axis: proportion of patients with symptom onset. X-axis: age. Trend difference was analyzed with log rank (p = 0.012), Breslow (p = 0.02), and Tarone-Ware (p = 0.02) tests. FUS, n = 54; SOD1, n = 164; TARDBP, n = 34.