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

J. Yan, H. X. Deng, N. Siddique, F. Fecto, W. Chen, Y. Yang, E. Liu, S. Donkervoort, J. G. Zheng, Y. Shi, K. B. Ahmeti, B. Brooks, W. K. Engel, T. Siddique*

*Corresponding author for this work

Research output: Contribution to journalArticle

138 Scopus citations

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 ∼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.

Original languageEnglish (US)
Pages (from-to)807-814
Number of pages8
JournalNeurology
Volume75
Issue number9
DOIs
StatePublished - Aug 31 2010

ASJC Scopus subject areas

  • Clinical Neurology

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    Yan, J., Deng, H. X., Siddique, N., Fecto, F., Chen, W., Yang, Y., Liu, E., Donkervoort, S., Zheng, J. G., Shi, Y., Ahmeti, K. B., Brooks, B., Engel, W. K., & Siddique, T. (2010). Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology, 75(9), 807-814. https://doi.org/10.1212/WNL.0b013e3181f07e0c