Elsevier

Neurobiology of Aging

Volume 32, Issue 3, March 2011, Pages 553.e23-553.e26
Neurobiology of Aging

Genetic reports abstract
A de novo missense mutation of the FUS gene in a “true” sporadic ALS case

https://doi.org/10.1016/j.neurobiolaging.2010.05.016Get rights and content

Abstract

Mutations in the Cu/Zn superoxide dismutase (SOD1), transactive response (TAR)-DNA binding protein (TARDBP) and fused in sarcoma (FUS) genes account for approximately 1 third of familial amyotrophic lateral sclerosis (ALS) cases. Mutations in these genes have been found in 1% to 2% of apparently sporadic cases. We present the first case of an ALS patient carrying a de novo missense mutation of the FUS gene (c.1561C>T, p.R521C). This report highlights the importance of screening ALS patients, both familial and sporadic, for FUS mutations and also suggests that de novo mutations is a relevant mechanism underlying sporadic neurodegenerative disease.

Introduction

Amyotrophic lateral sclerosis (ALS) is neurodegenerative disorder of adult life, characterized by a progressive loss of cortical, bulbar, and spinal motor neurons. Approximately 5%–10% of patients have a family history of disease, whereas the remaining 90%–95% of cases appear to occur sporadically in the community. To date, mutations in 3 genes have been described as common causes of familial ALS, namely SOD1 (OMIM 147450), TARDBP (OMIM 605078), and FUS (OMIM 137070) (Kwiatkowski et al., 2009, Rosen et al., 1993, Sreedharan et al., 2008, Vance et al., 2009). Mutations of these genes account for about approximately 1 third of familial ALS cases. In contrast, the genetics of sporadic ALS is poorly understood. Genome-wide association studies of ALS have failed to yield a single replicating locus (Valdmanis et al., 2009), although possible susceptibility loci have been proposed (van Es et al., 2009). Mutations in SOD1, FUS, and TARDBP have each been found in 1% to 2% of apparently sporadic cases, though it remains unclear if these cases are truly sporadic, or instead represent examples of familial ALS where the family history is not immediately obvious due to decreased disease penetrance or misdiagnosis in preceding generations (Chiò et al., 2008, Corrado et al., 2010, Lai et al., 2010, Sreedharan et al., 2008). There are 2 documented cases of genetically proven truly sporadic ALS patients, 1 resulting from a de novo SOD1 mutation (Alexander et al., 2002), and 1 heterozygous splice-site mutation in FUS intron 13 (IVS13-2A>G) (Dejesus-Hernandez et al., 2010.)

Here, we present a case of an ALS patient carrying a de novo missense mutation of the FUS gene.

Section snippets

Methods

While performing mutational screening of FUS in a large series of sporadic and familial ALS cases, we detected a young onset ALS patient carrying the p.R521C missense mutation (c.1561C>T) in exon 15 of FUS (Chiò et al., 2008, Lai et al., 2010). Because both his parents were still alive and not affected by ALS, we searched for the mutation in the parents and in the patient's brother.

Case history

The patient's family pedigree is shown in Fig. 1. The patient (Fig. 1. III 5) was a 38-year-old man who developed muscle weakness and atrophy at the shoulder girdle at the age of 34 years, spreading rapidly to involve the flexor and extensor neck muscles. Deep tendon reflexes were normal, with the exception of ankle jerk reflexes, which were hyperactive with clonus. Babinski and Hoffman signs were not present. He was cognitively normal. Neurophysiological examination demonstrated chronic and

Discussion

Here we report a proven case of de novo FUS mutation causing sporadic ALS. The parents and siblings did not carry the mutation, and highly informative polymorphic markers confirmed paternity and maternity. Furthermore, this particular mutation has previously been shown to segregate with disease in several ALS families, and has not been detected in a large number of neurologically normal controls (Kwiatkowski et al., 2009, Vance et al., 2009).

Our finding, together with our previous publication

Disclosure statement

All authors report no conflict of interest. Author's institutions have no contracts relating to this research through which it or any other organization may stand to gain financially now or in the future.

The study has been approved by the Institutional Board Review of each participating center. The patient and his family members signed a written informed consent.

Acknowledgements

Adriano Chiò had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We thank the patient and his family for having collaborated in this study.

This work was funded by grants of Fondazione Vialli e Mauro for ALS Research Onlus, Federazione Italiana Giuoco Calcio (FICG), and Ministero della Salute (Ricerca Sanitaria Finalizzata 2007) (Dr Chiò); and Ministero della Salute (Ricerca Sanitaria Finalizzata 2007) (Dr

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These authors contributed equally to this work.

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