Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort

Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Neurology (Impact Factor: 8.29). 10/2009; 73(15):1180-5. DOI: 10.1212/WNL.0b013e3181bbff05
Source: PubMed


Mutations in the FUS gene on chromosome 16 have been recently discovered as a cause of familial amyotrophic lateral sclerosis (FALS). This study determined the frequency and identities of FUS gene mutations in a cohort of Italian patients with FALS.
We screened all 15 coding exons of FUS for mutations in 94 Italian patients with FALS.
We identified 4 distinct missense mutations in 5 patients; 2 were novel. The mutations were not present in 376 healthy Italian controls and thus are likely to be pathogenic.
Our results demonstrate that FUS mutations cause approximately 4% of familial amyotrophic lateral sclerosis cases in the Italian population.

Download full-text


Available from: Peter C Sapp, Nov 10, 2014
23 Reads
  • Source
    • "Eventually, FUS was found to be the most characteristic marker of the remaining tau-negative and/ or TDP-43 negative FTLD cases, encompassing three closely related but distinct clinicopathological entities: atypical FTLD-U (aFTLD-U), neuronal intermediate filament inclusion disease (NIFID), and basophilic inclusion body disease (BIBD) (Munoz et al., 2009; Neumann et al., 2009a,b; Urwin et al., 2010). FUS mutations in patients with clinical FTLD are rare, and only four FUS mutations have so far been identified in patients with FTD-MND/ALS or in their families (Ticozzi et al., 2009; Blair et al., 2010; Broustal et al., 2010; Yan et al., 2010). Moreover, two cases with a pure FTD phenotype without motor neuron involvement Benussi et al. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease.
    Frontiers in Aging Neuroscience 09/2015; 7(171). DOI:10.3389/fnagi.2015.00171 · 4.00 Impact Factor
  • Source
    • "To date, more than 35 related FUS mutations were identified in ALS patients, with only two nonsense mutations reported (Belzil et al., 2011; Waibel et al., 2010). It is noteworthy that some ALS cases harboring FUS mutations also have Frontotemporal Lobar Degeneration (Blair et al., 2010; Ticozzi et al., 2009; Van Langenhove et al., 2010). In the literature, FUS is described as an RNA/DNA-binding protein, mainly located in the nucleus that is involved in multiple biological processes (Lagier-Tourenne et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Essential tremor (ET) is a prevalent neurological disorder of unknown etiology characterized by the presence of an action tremor that occurs during voluntary motion and affects primarily the upper limbs. The worldwide prevalence of the disease in the general population is 0.9%, increasing to 4.6% in individuals ≥ 65 years old. Standard pharmaceutical treatments are only moderately effective, reducing tremor amplitudes in ∼ 50% of patients, a phenomenon partly explained by the fact that the diagnosis of ET is based solely on clinical findings rather than biological markers. Furthermore, the pathophysiological origin of ET remains controversial, leading to heated debates as to whether it should be considered a neurodegenerative disorder or as a dynamic oscillatory disturbances of neurologic origin. Progress has been made in the understanding of its etiology as it is now accepted that genetic components must at least explain the familial cases of ET, and the evidence implicating the olivocerebellar and cerebello-thalamo-cortical pathways is strong. However, a strong disconnection between human genetics, pathophysiological, and mouse genetics studies exists in the field of ET, with little use of all the knowledge gathered from the different research disciplines. This review highlights our current knowledge on ET from both a human population and mouse genetics perspective hoping to reconcile evidence from both fields and leading to novel clues guiding future studies. We argue that better communication between researchers of different fields is warranted to define the biological origin of ET in the hope of leading to the development of better treatments.
    Progress in Neurobiology 05/2014; 119-120. DOI:10.1016/j.pneurobio.2014.05.001 · 9.99 Impact Factor
  • Source
    • "50 c.1561 C>T p.R521C Exon 15/RGG rich 31 6 Bulbar, spinal Parkinsonism and dementia (1) Africa, Australia, Canada, China, Europe, France, Germany, Italy, Japan, Netherlands, Spain, United Kingdom, USA [Belzil et al., 2009; Blair et al., 2010; Chì o et al., 2011b; Corrado et al., 2009a; Drepper et al., 2011; Groen et al., 2010; Kwiatkowski et al., 2009; Lai et al., 2010; Millecamps et al., 2010; Rademakers et al., 2010; Suzuki et al., 2010; Syriani et al., 2011; Ticozzi et al., 2009; van Blitterswijk et al., 2012; Vance et al., 2009; Yamamoto-Watanabe et al., 2010; Yan et al., 2010; Sproviero et al., 2012] 51 c.1561 C>G p.R521G Exon 15/RGG rich 6 2 Spinal None China, Europe, Italy, USA [Brown et al., 2012; Kwiatkowski et al., 2009; Sproviero et al., 2012; Ticozzi et al., 2009; Yan et al., 2010; Zou et al., 2012c] 52 c.1561 C>A p.R521S Exon 15/RGG rich 1 Bulbar None France [Millecamps et al., 2010] 53 c.1562 G>A p.R521H Exon 15/RGG rich 15 4 Spinal FTD (1) Australia, Belgium, Cambodia, China, France, Italy, Netherlands, Quebec, Taiwan, United Kingdom, USA [Belzil et al., 2009; Blair et al., 2010; Broustal et al., 2010; Groen et al., 2010; Kwiatkowski et al., 2009; Lai et al., 2010; Millecamps et al., 2010; Tsai et al., 2011; van Blitterswijk et al., 2012; Vance et al., 2009; Van Damme et al., 2010; Van Langenhove et al., 2010; Yan et al., 2010; Zou et al., 2012b] 54 c.1562 G>T p.R521L Exon 15/RGG rich 3 1 Spinal None China, Europe, France, Italy [Lattante et al., 2012; Millecamps et al., 2010; Yan et al., 2010; Zou et al., 2012b] 55 c.1564 A>G p.R522G "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in Sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database(LOVD) and is accessible online at,
    Human Mutation 06/2013; 34(6). DOI:10.1002/humu.22319 · 5.14 Impact Factor
Show more