Mutations in
            <i>FUS</i>
            cause FALS and SALS in French and French Canadian populations

Belzil, Véronique V.; Valdmanis, Paul N.; Dion, Patrick A.; Daoud, Hussein; Kabashi, Edor; Noreau, Anne; Gauthier, Julie; Hince, Pascale; Desjarlais, Anne; Bouchard, Jean‐Pierre; Lacomblez, Lucette; Salachas, François; Pradat, Pierre; Camu, William; Meininger, Vincent; Dupré, Nicolas; Rouleau, Guy A.

doi:10.1212/wnl.0b013e3181bbfeef

Cited by 122 publications

(120 citation statements)

References 10 publications

(15 reference statements)

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“…We detected 3 different missense mutations in 4 sporadic ALS cases (p. R521C, p. R521G, p. P525L) with a frequency of 1.25%, which is slightly higher than what has been previously reported (Belzil et al, 2009;Corrado et al, 2010;Ticozzi et al, 2009). However, all patients must be considered apparently sporadic because either there was no family member DNA available for testing or there was a lack of information about the patients' family trees.…”

Section: Discussionmentioning

confidence: 55%

FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis

Sproviero¹,

Bella²,

Mazzei³

et al. 2012

Neurobiology of Aging

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Fused in sarcoma (FUS) or translocation in liposarcoma (TLS), a DNA/RNA-binding protein, causes a dominant autosomal inherited form of amyotrophic lateral sclerosis (ALS), ALS 6. Its main role in neurodegeneration is highlighted by the presence of cytoplasmic accumulation of its mutant protein form in ALS patients. To further define the frequency and spectrum of FUS gene mutations, we have performed a molecular screening of a cohort of 327 Italian patients from Southern Italy with sporadic ALS (SALS). We identified 4 patients carrying 3 different missense mutations and several polymorphisms. Two different substitutions occurring in the same amino acidic position have been observed in 2 patients: R521G and R521C respectively; P525L mutation has been found in 2 additional cases. Most of the patients with FUS mutations showed early symptom onset and had short disease survival. We also detected 4 different polymorphic variants (3=-untranslated region [UTR] variant, c.*41GϾA; c.523ϩ3ins [GAGGTG];; and rs13331793) in 9 patients from within our cohort. This study underlines the importance of population-based mutation screening of newly identified genes.

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Section: Discussionmentioning

confidence: 55%

FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis

Sproviero¹,

Bella²,

Mazzei³

et al. 2012

Neurobiology of Aging

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“…[4][5][6][7][8][9] We found the FUS mutation in a Japanese family with FALS with the characteristics of early onset, rapid progress, high penetrance, degeneration of FALS with FUS mutation in Japan N Suzuki et al the multiple system, remarkable atrophy of the brainstem tegmentum and basophilic inclusion bodies in the autopsy. The immunohistochemical findings of the basophilic inclusion bodies of our case were recognized by using ubiquitin, but not by using antibodies to tau, neurofilament 11 or TDP-43.…”

Section: Discussionmentioning

confidence: 82%

“…3 Very recently, two groups of investigators reported the autosomal dominant form of FALS caused by fused in sarcoma (FUS) mutations, 4,5 following several reports of both familial and sporadic cases from Europe. [6][7][8][9] FUS is a nucleoprotein that functions in DNA and RNA metabolism. 10 In this study, we found a large Japanese FALS family with mutations in the FUS gene with the characteristics of early onset.…”

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confidence: 99%

FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion

et al. 2010

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Mutations in the fused in sarcoma (FUS, also known as translated in liposarcoma) gene have been recently discovered to be associated with familial amyotrophic lateral sclerosis (FALS) in African, European and American populations. In a Japanese family with FALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with FALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, followed by dysarthria, dysphagia, spasticity and muscle atrophy. The average age of death was 37.2 years. Neuropathological examination of the index case revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We screened 40 FALS families in Japan and found 4 mutations (S513P, K510E, R514S, H517P) in exon 14 and 15 of FUS. Even in Asian races, FALS with FUS mutations may have the common characteristics of early onset, rapid progress and high penetrance rate, although in patients with the S513P mutation it was late-onset. Degeneration in multiple systems and cytoplasmic basophilic inclusion bodies were found in the autopsied cases. 3 Very recently, two groups of investigators reported the autosomal dominant form of FALS caused by fused in sarcoma (FUS) mutations, 4,5 following several reports of both familial and sporadic cases from Europe. 6-9 FUS is a nucleoprotein that functions in DNA and RNA metabolism. 10 In this study, we found a large Japanese FALS family with mutations in the FUS gene with the characteristics of early onset. In addition, we report four mutations of the FUS gene in Japanese FALS. CASE REPORT OF THE INDEX CASEThe patient (indicated by arrow in Figure 1a) was a Japanese man with autosomal dominant hereditary burden as described in a previous report. 11 His family history revealed 23 patients with FALS over four generations (Figure 1a). He developed muscle weakness of the distal part of the right upper extremity at age 30, followed by dysarthria, dysphagia, muscle weakness and atrophy in the four extremities, spasticity, hyperreflexia and Babinski's sign. His sensory, cerebellar and higher cortical functions were not affected. At age 31 (17 months after onset) he needed ventilatory support. At age 40, he died of bronchopneumonia. MATERIALS AND METHODSAll patients of FALS without the superoxide dismutase 1 mutation and healthy controls provided informed consent, after which DNA extraction and genotyping were performed using standard protocols as described elsewhere. 12 We sequenced all exons in 40 unrelated FALS families with the characteristics of an autosomal dominant trait in Japan. Sections of 5 mm thickness were taken from the midbrain of the index case and stained as described elsewhere. 5 Rabbit polyclonal anti-TDP-43 (ProteinTech, Chicago, IL, USA) and rabbit polyclonal anti-ubiquitin (Abcam, Cambridge, MA, USA) antibodies were used. The study was approved by the ethic...

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“…Deletions of serines (S57 and S96) in FUS LC are associated with subtypes of ALS (Belzil et al , 2009; Yan et al , 2010). We identified S96 as a site phosphorylated in FUS.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

et al. 2017

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Neuronal inclusions of aggregated RNA‐binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation‐prone, yeast prion‐like, low sequence‐complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in‐cell phosphorylation sites across FUS LC. We show that both phosphorylation and phosphomimetic variants reduce its aggregation‐prone/prion‐like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self‐interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS‐associated cytotoxicity. Hence, post‐translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.

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Mutations in FUS cause FALS and SALS in French and French Canadian populations

Abstract: Background:The identification of mutations in the TARDBP and more recently the identification of

Cited by 122 publications

References 10 publications

FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis

FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis

FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

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