TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis
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...For these reasons, the recent identification of mutations in TDP-43 (encoded by TARDBP) (Kabashi et al., 2008; Sreedharan et al., 2008) and the related RNA-binding protein fused in sarcoma (FUS) (Kwiatkowski et al., 2009; Vance et al., 2009) in 5% of familial ALS patients has significantly shifted…...
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...MC Clinical FTD Familial 171 20 (11.7) 13 (7.6) 12 (6.3) n/a n/a n/a Sporadic 203 6 (3.0) 6 (3.0) 3 (1.5) n/a n/a n/a MCF Clinical ALS Familial 34 8 (23.5) n/a n/a 4 (11.8) 1 (2.9) 1 (2.9) Sporadic 195 8 (4.1) n/a n/a 0 (0.0) 2 (1.0) 3 (1.5) ALS = amyotrophic lateral sclerosis; c9FTD/ALS = (GGGGCC)n repeat expansion at chromosome 9p identified in this study; FTD = frontotemporal dementia; FTLD-TDP = frontotemporal lobar degeneration with TDP-43 pathology; FUS = fused in sarcoma gene; GRN = progranulin gene; MAPT =microtubule-associated protein tau gene; MC =Mayo Clinic; MCF =Mayo Clinic Florida; n/a = not assessed; SOD1 = superoxide dismutase 1 gene; TARDBP = TAR DNA-binding protein 43 gene; UBC = University of British Columbia. a Includes 22 individuals for which no information on family history was available. unrelated expanded repeat carriers had at least one copy of the ‘‘risk’’ haplotype (100...
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...Importantly, a direct comparison of the frequency of repeat expansions in C9ORF72 with mutations in SOD1, TARDBP, and FUS revealed GGGGCC expansions to be the most common genetic cause of sporadic and familial ALS in our clinical series (Table 1)....
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...For these reasons, the recent identification of mutations in TDP-43 (encoded by TARDBP) (Kabashi et al., 2008; Sreedharan et al., 2008) and the related RNA-binding protein fused in sarcoma (FUS) (Kwiatkowski et al., 2009; Vance et al., 2009) in 5% of familial ALS patients has significantly shifted the focus of ALS research and implicated abnormal RNA processing as a critical process in ALS pathogenesis (Lagier-Tourenne et al., 2010)....
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...This familial association is not well explained by the currently recognized genetic defects; GRNmutations are not associated with significant motor neuron deficits, while patients carrying mutations in SOD1, TARDBP, or FUS are rarely affected by FTD. Linkage analysis in several autosomal-dominant families in which affected members develop either ALS or FTD or both, and where the pathology is consistently TDP positive, have suggested a major locus for FTD/ALS on chromosome 9p21....
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