S.W. and M.N. contributed equally to the manuscript.
Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany
Article first published online: 6 DEC 2012
© 2012 The Author(s) European Journal of Neurology © 2012 EFNS
European Journal of Neurology
Volume 20, Issue 3, pages 540–546, March 2013
How to Cite
Waibel, S., Neumann, M., Rosenbohm, A., Birve, A., Volk, A. E., Weishaupt, J. H., Meyer, T., Müller, U., Andersen, P. M. and Ludolph, A. C. (2013), Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany. European Journal of Neurology, 20: 540–546. doi: 10.1111/ene.12031
- Issue published online: 14 FEB 2013
- Article first published online: 6 DEC 2012
- Manuscript Accepted: 10 OCT 2012
- Manuscript Received: 13 JUN 2012
- BMBF-funded German Network. Grant Numbers: 31003A-132864, CRSII2 136222, 01GI1005B
- Ulla-Carin Lindquist ALS-Foundation
- Charcot Foundation. Grant Numbers: 31003A-132864, CRSII2 136222, 01GI1005B
- Charcot Foundation for ALS Research
- Swiss National Science Foundation. Grant Numbers: 31003A-132864, CRSII2 136222
- German Federal Ministry of Education and Research. Grant Number: 01GI1005B
- Stavros-Niarchos Foundation
- Synapsis Foundation
- Hans&Ilse Breuer Foundation
- Swedish Medical Research Council
- Bertill Hållsten Brain Research Foundation
- amyotrophic lateral sclerosis twin monozygosity concordance;
- familial amyotrophic lateral sclerosis;
- genetic counselling;
- truncating mutation
Background and purpose
Mutations in the FUS/TLS have been associated with amyotrophic lateral sclerosis (ALS) in a few percent of patients.
We screened 184 familial (FALS) and 200 sporadic German patients with ALS for FUS/TLS mutations by sequence analysis of exons 5, 6 and 13–15. We compared the phenotypes of patients with different FUS/TLS mutations.
We identified three missense mutations p.K510R, p.R514G, p.R521H, and the two truncating mutations p.R495X and p.G478LfsX23 in samples from eight pedigrees. Both truncating mutations were associated with young onset and very aggressive disease courses, whereas the p.R521H, p.R514G and in particular the p.K510R mutation showed a milder phenotype with disease durations ranging from 3 years to more than 26 years, the longest reported for a patient with a FUS/TLS mutation. Also, in a pair of monozygous twins with the p.K510R mutation, a remarkable similar disease course was observed.
Mutations in FUS/TLS account for 8.7% (16 of 184) of FALS in Germany. This is a higher prevalence than reported from other countries. Truncating FUS/TLS mutations result in a more severe phenotype than most missense mutations. The wide phenotypic differences have implications for genetic counselling.