The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Stephanie Millecamps - One of the best experts on this subject based on the ideXlab platform.
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phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations
Neurology, 2012Co-Authors: Philippe Corcia, Stephanie Millecamps, Paul N Valdmanis, C Lionnet, Helene Blasco, Kevin Mouzat, Hussein Daoud, Veronique V Belzil, Raul Juntas Morales, Nicolas PageotAbstract:Objective: To describe the phenotype and phenotype–genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. Methods: French TARDBP + patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP + cases from the literature. Genotype–phenotype correlations were studied for the most frequent TARDBP mutations. Results: In TARDBP + patients, onset was earlier ( p = 0.0003), upper limb (UL) onset was predominant ( p = 0.002), and duration was longer ( p = 0.0001) than in patients with SALS. TARDBP + and SOD1 + groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP + and 74.1% on lower limbs for SOD1 + ( p p = 0.02). The type of mutation influenced survival ( p TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). Conclusion: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.
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phenotype difference between als patients with expanded repeats in c9orf72 and patients with mutations in other als related genes
Journal of Medical Genetics, 2012Co-Authors: Stephanie Millecamps, Isabelle Le Ber, Severine Boillee, Danielle Seilhean, Elisa Teyssou, Marine Giraudeau, Carine Moigneu, Nadia Vandenberghe, Veronique Danelbrunaud, Philippe CorciaAbstract:Background Expanded GGGGCC hexanucleotide repeats in the promoter of the C9ORF72 gene have recently been identified in frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and ALS-FTD and appear as the most common genetic cause of familial (FALS) and sporadic (SALS) forms of ALS. Methods We searched for the C9ORF72 repeat expansion in 950 French ALS patients (225 FALS and 725 SALS) and 580 control subjects and performed genotype-phenotype correlations. Results The repeat expansion was present in 46% of FALS, 8% of SALS and 0% of controls. Phenotype comparisons were made between FALS patients with expanded C9ORF72 repeats and patients carrying another ALS-related gene ( SOD1, TARDBP, FUS ) or a yet unidentified genetic defect. SALS patients with and without C9ORF72 repeat expansions were also compared. The C9ORF72 group presented more frequent bulbar onset both in FALS (p<0.0001 vs SOD1 , p=0.002 vs TARDBP , p=0.011 vs FUS , p=0.0153 vs other FALS) and SALS (p=0.047). FALS patients with C9ORF72 expansions had more frequent association with FTD than the other FALS patients (p<0.0001 vs SOD1 , p=0.04 vs TARDBP , p=0.004 vs FUS , p=0.03 vs other FALS). C9ORF72 -linked FALS patients presented an older age of onset than SOD1 (p=0.0139) or FUS mutation (p<0.0001) carriers. Disease duration was shorter for C9ORF72 expansion carriers than for SOD1 (p<0.0001) and TARDBP (p=0.0242) carriers, other FALS (p<0.0001) and C9ORF72 -negative SALS (p=0.0006). Conclusions Our results confirm the major role of expanded repeats in C9ORF72 as causative for ALS and provide evidence for specific phenotypic aspects compared to patients with other ALS-related genes.
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abnormal tdp 43 and fus proteins in muscles of sporadic ibm similarities in a TARDBP linked als patient
Journal of Neurology Neurosurgery and Psychiatry, 2011Co-Authors: Aurelio Hernandez Lain, Stephanie Millecamps, Danielle Seilhean, François Salachas, Gaelle Bruneteau, Odile Dubourg, Lucette Lacomblez, Eric Leguern, Charles Duyckaerts, Vincent MeiningerAbstract:Abnormal protein deposits are observed in the cytoplasm of sporadic inclusion body myositis (s-IBM) muscle. A number of proteins known to be included in s-IBM aggregates have also been described in various neurodegenerative diseases, including ubiquitin, β amyloid peptide, α -synuclein, phosphorylated τ and TAR DNA-binding protein (TDP-43). In the central nervous system (CNS), TDP-43 aggregates are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive neuronal inclusions. Numerous dominant mutations in the TARDBP gene encoding TDP-43 protein have been reported in ALS cases, demonstrating that TDP-43 abnormalities could directly trigger neurodegeneration. The recent discovery of mutations in the gene encoding Fused in Sarcoma (FUS) protein, which shares functional and structural homology with TDP-43, has strengthened the prominence of gene expression-mediating proteins in ALS pathogenesis. Whether muscle TDP-43 aggregates observed in s-IBM are just trashed protein, or whether they are pathogenic, particularly trough RNA metabolism disturbances, remains unknown. We hypothesised that FUS protein could be altered in TDP-43 positive muscles of s-IBM. For this purpose, we investigated the protein muscle expression of TDP-43 and FUS in s-IBM compared to sporadic amyotrophic lateral sclerosis (SALS) patients (including one patient with TARDBP gene mutation) and controls. We report abnormal FUS and TDP-43 fragments in s-IBM and TARDBP -linked disease. Five patients with s-IBM, five patients with …
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sod1 ang vapb TARDBP and fus mutations in familial amyotrophic lateral sclerosis genotype phenotype correlations
Journal of Medical Genetics, 2010Co-Authors: Stephanie Millecamps, Agnès Camuzat, François Salachas, Lena Guillotnoel, Cecile Cazeneuve, Paul H Gordon, Bernard Bricka, Odile Russaouen, Gaelle Bruneteau, Pierrefrancois PradatAbstract:Background. Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). Methods. We estimated the relative contributions of the different mutations to ALS by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. Results. We found 31 pathogenic missense mutations in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harbored ANG variants. We identified one family of Japanese origin with the P56S VAPB mutation. Seven novel mutations (3 in SOD1, 2 in TARDBP, 2 in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including 5 pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other FALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations) and in life span (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease-onset than those presenting with more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. Conclusions. This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
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sod1 ang vapb TARDBP and fus mutations in familial amyotrophic lateral sclerosis genotype phenotype correlations
Journal of Medical Genetics, 2010Co-Authors: Stephanie Millecamps, Agnès Camuzat, François Salachas, Lena Guillotnoel, Cecile Cazeneuve, Paul H Gordon, Bernard Bricka, Odile Russaouen, Gaelle Bruneteau, Pierrefrancois PradatAbstract:BACKGROUND: Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). METHODS: The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. RESULTS: 31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. CONCLUSIONS: This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
Pierrefrancois Pradat - One of the best experts on this subject based on the ideXlab platform.
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sod1 ang vapb TARDBP and fus mutations in familial amyotrophic lateral sclerosis genotype phenotype correlations
Journal of Medical Genetics, 2010Co-Authors: Stephanie Millecamps, Agnès Camuzat, François Salachas, Lena Guillotnoel, Cecile Cazeneuve, Paul H Gordon, Bernard Bricka, Odile Russaouen, Gaelle Bruneteau, Pierrefrancois PradatAbstract:Background. Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). Methods. We estimated the relative contributions of the different mutations to ALS by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. Results. We found 31 pathogenic missense mutations in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harbored ANG variants. We identified one family of Japanese origin with the P56S VAPB mutation. Seven novel mutations (3 in SOD1, 2 in TARDBP, 2 in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including 5 pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other FALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations) and in life span (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease-onset than those presenting with more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. Conclusions. This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
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sod1 ang vapb TARDBP and fus mutations in familial amyotrophic lateral sclerosis genotype phenotype correlations
Journal of Medical Genetics, 2010Co-Authors: Stephanie Millecamps, Agnès Camuzat, François Salachas, Lena Guillotnoel, Cecile Cazeneuve, Paul H Gordon, Bernard Bricka, Odile Russaouen, Gaelle Bruneteau, Pierrefrancois PradatAbstract:BACKGROUND: Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). METHODS: The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. RESULTS: 31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. CONCLUSIONS: This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
Pamela J Shaw - One of the best experts on this subject based on the ideXlab platform.
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TARDBPl splicing rescues motor neuron and axonal development in a mutant TARDBP zebrafish
Human Molecular Genetics, 2013Co-Authors: Channa Hewamadduma, Andrew J Grierson, Taylur P, Luyuan Pan, Cecilia B Moens, Philip W Ingham, Tennore Ramesh, Pamela J ShawAbstract:Mutations in the transactive response DNA binding protein-43 (TARDBP/TDP-43) gene, which regulates transcription and splicing, causes a familial form of amyotrophic lateral sclerosis (ALS). Here, we characterize and report the first TARDBP mutation in zebrafish, which introduces a premature stop codon (Y220X), eliminating expression of the TARDBP protein. Another TARDBP ortholog, TARDBPl, in zebrafish is shown to encode a TARDBP-like protein which is truncated compared with TARDBP itself and lacks part of the C-terminal glycine-rich domain (GRD). Here, we show that TARDBP mutation leads to the generation of a novel TARDBPl splice form (TARDBPl-FL) capable of making a full-length TARDBP protein (TARDBPl-FL), which compensates for the loss of TARDBP. This finding provides a novel in vivo model to study TDP-43-mediated splicing regulation. Additionally, we show that elimination of both zebrafish TARDBP orthologs results in a severe motor phenotype with shortened motor axons, locomotion defects and death at around 10 days post fertilization. The TARDBP/TARDBPl knockout model generated in this study provides an excellent in vivo system to study the role of the functional loss of TARDBP and its involvement in ALS pathogenesis.
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a novel alternative splicing event rescues the mutant TARDBP phenotype in a zebrafish model of tdp 43 related amyotrophic lateral sclerosis als p03 180
Neurology, 2012Co-Authors: Channa Hewamadduma, Andrew J Grierson, Taylur P, Luyuan Pan, Cecilia B Moens, Philip W Ingham, Tennore Ramesh, Pamela J ShawAbstract:Objective: To study the role of TDP-43 in a zebrafish model of Amyotrophic Lateral Sclerosis. Background Amyotrophic lateral sclerosis is a devastating neurodegenerative condition. TDP-43 positive inclusions, have been reported as the hallmark pathology of ALS and FTLD-U. A major RNA processing function of TDP-43 is regulation of splicing. In mouse and drosophila models, TDP-43 has been shown to be important during early embryogenesis. TDP-43 has been observed to mis-localize from the nucleus to the cytoplasm of the surviving motor neurons in the postmortem brain and spinal cord tissues. Thus raising the possibility that the loss of nuclear function of TDP-43 might be responsible in the disease pathogenesis. Zebrafish is a robust vertebrate model, which we have used as a platform to study the loss of function effects of TDP-43. Design/Methods: We identified TARDBP and TARDBPl as zebrafish orthologues of TARDBP. We have used Antisense Morpholino Oligonucleotides (AMO) to transiently knock down TARDBP and TARDBPl. We generated TARDBP mutant, Y220X, which results in a nonsense mediated decay of TARDBP. We studied the motor neurons, axonal out growth, swimming behavior, survival and neuromuscular junction architecture, immuno blotting, immunohistochemistry and qRT-PCR to characterize and confirm our findings. Results: In a transient knockout of TARDBP resulted in a phenotype similar to ALS. The stable homozygous TARDBP Y220X mutant zebrafish shows significant reduction in weight and length at 6 months of age (p TARDBP and TARDBPl sequences we have discovered a novel alternative splicing event and a resultant novel splice variant of TARDBPl. Conclusions: We have demonstrated that TARDBP and TARDBPl are essential for the normal development of the zebrafish motor neurons. Loss of TARDBP results in a novel alternative splice isoform and up regulation of the same, thus providing an in vivo model of TDP-43 auto-regulation. Understanding this novel regulatory loop could play a key role in the successful generation of zebrafish models relating to ALS genes such as TDP-43 and FUS-1, which have important RNA processing functions. Supported by: CAH is funded by an MRC Clinical Research Fellowship from MRC Centre for Developmental Biomedical Genetics (CDBG). Disclosure: Dr. Hewamadduma has nothing to disclose. Dr. Grierson has nothing to disclose. Dr. Moens has nothing to disclose. Dr. Helde has nothing to disclose. Dr. Ingham has nothing to disclose. Dr. Ramesh has nothing to disclose. Dr. Shaw has received personal compensation for activities with Sanofi Aventis. Dr. Shaw has received research support from Trophos and Biogen Idec.
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160 novel in vitro and in vivo models of als associated with tdp 43 proteinopathy
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Channa Hewamadduma, C A A Higgenbottom, C Moens, K Helde, R Raman, R Tennore, Andrew J Grierson, Pamela J ShawAbstract:Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative condition, which results in death. TDP-43, has been implicated in sALS and fALS, as well as fronto temporal dementia with ubiquitinated inclusions (FTLD-U). Loss of TDP-43 function has been associated with early lethality during embryogenesis of both mice and drosophila models. Fibroblasts obtained from the patients carrying mutations in the TARDBP gene provide a vital tool in investigation of TDP-43 in ALS at native levels of the mutant protein. Here we show that fibroblasts obtained from cases with mutations in TARDBP gene have similar pathological correlates to surviving motor neurons in pathological samples of ALS cases. In keeping with the findings in post mortem material from ALS cases, relative clearing of nuclear TDP-43 was noted in mTDP-43 fibroblasts (p
Edor Kabashi - One of the best experts on this subject based on the ideXlab platform.
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TARDBP and fus mutations associated with amyotrophic lateral sclerosis summary and update
Human Mutation, 2013Co-Authors: Serena Lattante, Edor Kabashi, Guy A RouleauAbstract:Mutations in the TAR DNA Binding Pro- teingene(TARDBP),encodingtheproteinTDP-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 frontotemporaldementia(FTD)inclusionbodies,andsub- sequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mu- tations have been described in a large number of famil- ial (FALS) and sporadic (SALS) patients. Fused in sar- coma (FUS) was found to be responsible for a previ- ously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a struc- tural 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 mu- tant TDP-43 and FUS may cause motor neuron degen- eration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characteriza- tion of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron de- generation occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submit- ted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS.
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fus and TARDBP but not sod1 interact in genetic models of amyotrophic lateral sclerosis
PLOS Genetics, 2011Co-Authors: Edor Kabashi, Alexandra Lissouba, Meijiang Liao, Edna Brustein, Valérie Bercier, Guy A Rouleau, Pierre DrapeauAbstract:Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS–related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS–related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish TARDBP and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the TARDBP knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of TARDBP or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1.
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gain and loss of function of als related mutations of TARDBP tdp 43 cause motor deficits in vivo
Human Molecular Genetics, 2010Co-Authors: Edor Kabashi, Valérie Bercier, Li Lin, Miranda L Tradewell, Patrick A Dion, Patrick Bourgouin, Daniel Rochefort, Samar Bel Hadj, Heather D Durham, Christine Vande VeldeAbstract:TDP-43 has been found in inclusion bodies of multiple neurological disorders, including amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease and Alzheimer's disease. Mutations in the TDP-43 encoding gene, TARDBP, have been subsequently reported in sporadic and familial ALS patients. In order to investigate the pathogenic nature of these mutants, the effects of three consistently reported TARDBP mutations (A315T, G348C and A382T) were tested in cell lines, primary cultured motor neurons and living zebrafish embryos. Each of the three mutants and wild-type (WT) human TDP-43 localized to nuclei when expressed in COS1 and Neuro2A cells by transient transfection. However, when expressed in motor neurons from dissociated spinal cord cultures these mutant TARDBP alleles, but less so for WT TARDBP, were neurotoxic, concomitant with perinuclear localization and aggregation of TDP-43. Finally, overexpression of mutant, but less so of WT, human TARDBP caused a motor phenotype in zebrafish (Danio rerio) embryos consisting of shorter motor neuronal axons, premature and excessive branching as well as swimming deficits. Interestingly, knock-down of zebrafisfh TARDBP led to a similar phenotype, which was rescued by co-expressing WT but not mutant human TARDBP. Together these approaches showed that TARDBP mutations cause motor neuron defects and toxicity, suggesting that both a toxic gain of function as well as a novel loss of function may be involved in the molecular mechanism by which mutant TDP-43 contributes to disease pathogenesis.
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contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis
Journal of Medical Genetics, 2008Co-Authors: Hussein Daoud, Edor Kabashi, Paul N Valdmanis, Patrick A Dion, Nicolas Dupre, William Camu, Vincent Meininger, Guy A RouleauAbstract:Aims and background: Mutations in the TARDBP gene, which encodes the TAR DNA binding protein (TDP-43), have been described in individuals with familial and sporadic amyotrophic lateral sclerosis (ALS). We screened the TARDBP gene in 285 French sporadic ALS patients to assess the frequency of TARDBP mutations in ALS. Results: Six individuals had potentially deleterious mutations of which three were novel including a Y374X truncating mutation and P363A and A382P missense mutations. This suggests that TARDBP mutations may predispose to ALS in approximately 2% of the individuals followed in this study. Conclusion: Our findings, combined with those from other collections, brings the total number of mutations in unrelated ALS patients to 17, further suggesting that mutations in the TARDBP gene have an important role in the pathogenesis of ALS.
François Salachas - One of the best experts on this subject based on the ideXlab platform.
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abnormal tdp 43 and fus proteins in muscles of sporadic ibm similarities in a TARDBP linked als patient
Journal of Neurology Neurosurgery and Psychiatry, 2011Co-Authors: Aurelio Hernandez Lain, Stephanie Millecamps, Danielle Seilhean, François Salachas, Gaelle Bruneteau, Odile Dubourg, Lucette Lacomblez, Eric Leguern, Charles Duyckaerts, Vincent MeiningerAbstract:Abnormal protein deposits are observed in the cytoplasm of sporadic inclusion body myositis (s-IBM) muscle. A number of proteins known to be included in s-IBM aggregates have also been described in various neurodegenerative diseases, including ubiquitin, β amyloid peptide, α -synuclein, phosphorylated τ and TAR DNA-binding protein (TDP-43). In the central nervous system (CNS), TDP-43 aggregates are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive neuronal inclusions. Numerous dominant mutations in the TARDBP gene encoding TDP-43 protein have been reported in ALS cases, demonstrating that TDP-43 abnormalities could directly trigger neurodegeneration. The recent discovery of mutations in the gene encoding Fused in Sarcoma (FUS) protein, which shares functional and structural homology with TDP-43, has strengthened the prominence of gene expression-mediating proteins in ALS pathogenesis. Whether muscle TDP-43 aggregates observed in s-IBM are just trashed protein, or whether they are pathogenic, particularly trough RNA metabolism disturbances, remains unknown. We hypothesised that FUS protein could be altered in TDP-43 positive muscles of s-IBM. For this purpose, we investigated the protein muscle expression of TDP-43 and FUS in s-IBM compared to sporadic amyotrophic lateral sclerosis (SALS) patients (including one patient with TARDBP gene mutation) and controls. We report abnormal FUS and TDP-43 fragments in s-IBM and TARDBP -linked disease. Five patients with s-IBM, five patients with …
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sod1 ang vapb TARDBP and fus mutations in familial amyotrophic lateral sclerosis genotype phenotype correlations
Journal of Medical Genetics, 2010Co-Authors: Stephanie Millecamps, Agnès Camuzat, François Salachas, Lena Guillotnoel, Cecile Cazeneuve, Paul H Gordon, Bernard Bricka, Odile Russaouen, Gaelle Bruneteau, Pierrefrancois PradatAbstract:BACKGROUND: Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). METHODS: The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. RESULTS: 31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. CONCLUSIONS: This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
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sod1 ang vapb TARDBP and fus mutations in familial amyotrophic lateral sclerosis genotype phenotype correlations
Journal of Medical Genetics, 2010Co-Authors: Stephanie Millecamps, Agnès Camuzat, François Salachas, Lena Guillotnoel, Cecile Cazeneuve, Paul H Gordon, Bernard Bricka, Odile Russaouen, Gaelle Bruneteau, Pierrefrancois PradatAbstract:Background. Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). Methods. We estimated the relative contributions of the different mutations to ALS by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. Results. We found 31 pathogenic missense mutations in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harbored ANG variants. We identified one family of Japanese origin with the P56S VAPB mutation. Seven novel mutations (3 in SOD1, 2 in TARDBP, 2 in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including 5 pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other FALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations) and in life span (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease-onset than those presenting with more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. Conclusions. This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
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TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration
Annals of neurology, 2009Co-Authors: Lina Benajiba, Isabelle Le Ber, Agnès Camuzat, M. Lacoste, Catherine Thomas-antérion, Philippe Couratier, Solenn Legallic, François Salachas, Didier Hannequin, Marielle DecoususAbstract:TDP-43 (TAR-DNA binding protein) aggregates in neuronal inclusions in motoneuron disease (MND), as well as in frontotemporal lobar degeneration (FTLD) and FTLD associated with MND (FTLD-MND). Mutations in TARDBP gene, coding for TDP-43, were found in patients with pure MND. We now describe TARDBP mutations in two patients with FTLD-MND, presenting with a behavioral variant of FTLD and semantic dementia, suggesting that TDP-43 may also have a direct pathogenic role in FTLD disorders.
