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TARDBP and FUS Mutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update
Author(s) -
Lattante Serena,
Rouleau Guy A.,
Kabashi Edor
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22319
Subject(s) - tardbp , amyotrophic lateral sclerosis , biology , missense mutation , frontotemporal dementia , genetics , mutation , gene , c9orf72 , neurodegeneration , frontotemporal lobar degeneration , mutant , trinucleotide repeat expansion , disease , allele , dementia , pathology , sod1 , medicine
Mutations in the TAR DNA B inding P rotein 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 ALS 6 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 m RNA 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 have been submitted to a database based on the L eiden O pen (source) V ariation D atabase ( LOVD ) and is accessible online at www.lovd.nl/TARDBP , www.lovd.nl/FUS .