A patient carrying a homozygous p.A382T TARDBP missense mutation shows a syndrome including ALS, extrapyramidal symptoms, and FTD

Borghero, Giuseppe; Floris, Gianluca; Cannas, Antonino; Marrosu, Maria Giovanna; Murru, Maria Rita; Costantino, E; Parish, Leslie D.; Pugliatti, Maura; Ticca, Anna; Traynor, Brian J.; Calvo, Andrea; Cammarosano, Stefania; Moglia, Cristina; Cistaro, Angelina; Brunetti, Maura; Restagno, Gabriella; Chiò, Adriano

doi:10.1016/j.neurobiolaging.2011.06.009

Cited by 48 publications

(34 citation statements)

References 10 publications

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“…Of these, two patients carried C9ORF72 mutation, three carried a TARDBP p.A382T heterozygous missense mutation, one patient had a TARDBP p.A382T homozygous missense mutation (Borghero et al, 2011), and four did not carry a known mutations. Eight of these patients (80.0%) had comorbid FTD (p=0.0001).…”

Section: Resultsmentioning

confidence: 99%

Genetic architecture of ALS in Sardinia

Borghero

Pugliatti

Marrosu

et al. 2014

Neurobiology of Aging

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Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic ALS provide unique information on the genetics of the disease. Our aim was to describe the genetic profile of a consecutive series of ALS patients of Sardinian ancestry. All ALS patients of Sardinian ancestry, identified between 2008 and 2013 through the ITALSGEN consortium, were eligible to be included in the study. Patients and controls underwent the analysis of TARDBP, C9ORF72, SOD1, and FUS genes. Genetic mutations were identified in 155 out of 375 Sardinian ALS cases (41.3%), more commonly the p.A382T and p.G295S mutations of TARDBP, and the GGGGCC hexanucleotide repeat expansion of C9ORF72. One patient had both p.G295S and p.A382T mutation of TARDBP and eight carried both the heterozygous p.A382T mutation of TARDBP and a repeat expansion of C9ORF72. Patients carrying the p.A382T and the p.G295S mutations of TARDBP and the C9ORF72 repeat expansion shared distinct haplotypes across these loci. Patients with co-occurrence of C9ORF72 and TARDBP p.A382T missense mutation had a significantly lower age at onset and shorter survival. More than 40% of all cases on the island of Sardinia carry a mutation of an ALS-related gene, representing the highest percentage of ALS cases genetically explained outside of Scandinavia. Clinical phenotypes associated with different genetic mutations show some distinctive characteristics, but the heterogeneity between and among families carrying the same mutations implies that ALS manifestation is influenced by other genetic and non-genetic factors.

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Section: Resultsmentioning

confidence: 99%

Genetic architecture of ALS in Sardinia

Borghero

Pugliatti

Marrosu

et al. 2014

Neurobiology of Aging

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“…TDP-43 spontaneously forms aggregates; mutations within the CTD (Q331K, M337V, Q343R, N345K, R361S, N390D) increase the number of aggregates, promote toxicity in vivo , and accelerate aggregation of recombinant TDP-43 in vitro. In addition, a mutation causative of ALS and FTLD (A328T) has also been found in patients with PD, as well as in patients with FTD with Parkinsonism (Borghero et al, 2011; Cannas et al, 2013). …”

Section: Neurotoxicity Of Tdp-43/ Fusmentioning

confidence: 99%

“…While the location/distribution of TDP-43 aggregates differ between ALS (spinal cord) and FTLD (more widespread in the brain including frontal and temporal lobes), the familial mutations in TARDBP are unique to ALS and are not found in other neurodegenerative disorders including FTLD (Blokhuis et al, 2013; Brouwers et al, 2010; Rutherford et al, 2008; Van Deerlin et al, 2008). However, some of the common TARDBP mutations, presumably involving vulnerable residues for somatic mutations were reported in a small number of sporadic FTLD cases (Benajiba et al, 2009; Borghero et al, 2011; Borroni et al, 2009; Chiang et al, 2012; Chio et al, 2010; Corrado et al, 2009; Kovacs et al, 2009). Similar scenario may occur in other neurodegenerative diseases involving TDP-43 pathology such as inclusion body myositis and Alexander disease.…”

Section: Neurotoxicity Of Tdp-43/ Fusmentioning

confidence: 99%

TDP-43/FUS in motor neuron disease: Complexity and challenges

Guerrero

Wang

Mitra

et al. 2016

Progress in Neurobiology

107

122

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Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

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“…To date, 15 cases presenting with parkinsonism as part of their disease phenotype caused by TDP-43 mutations have been reported (Table 1) [8, 20, 21, 22]. Quadri and colleagues reported two cases manifesting parkinsonism and FTD, and a single case with PD from the same family due to TDP-43 p.A382T mutation [8].…”

Section: Discussionmentioning

confidence: 99%

TARDBP mutations in Parkinson's disease

Rayaprolu

Fujioka

Traynor

et al. 2013

Parkinsonism & Related Disorders

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Mutations of the TARDBP gene encoding TDP-43 protein have been shown to cause amyotrophic lateral sclerosis and have been reported to present with clinical heterogeneity including parkinsonism. In addition, TDP-43 pathology has been observed across a spectrum of neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Herein we report the presence of a TDP-43 mutation in a patient with a clinical diagnosis of Parkinson’s disease. The TDP-43 p.N267S substitution has been previously implicated in both amyotrophic lateral sclerosis and behavioral variant frontotemporal dementia. Our findings widen the phenotypic presentation for the TDP-43 p.N267S substitution and support a possible role for rare TDP-43 mutations presenting with Parkinson’s disease.

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A patient carrying a homozygous p.A382T TARDBP missense mutation shows a syndrome including ALS, extrapyramidal symptoms, and FTD

Cited by 48 publications

References 10 publications

Genetic architecture of ALS in Sardinia

Genetic architecture of ALS in Sardinia

TDP-43/FUS in motor neuron disease: Complexity and challenges

TARDBP mutations in Parkinson's disease

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