TARDBPandFUSMutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update

Abstract

Mutations in the TAR DNA Binding Protein 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 ALS6 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 mRNA 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 Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS.

UBE2E Ubiquitin-conjugating Enzymes and Ubiquitin Isopeptidase Y Regulate TDP-43 Protein Ubiquitination

“…To date, 48 mutations in the human gene encoding TDP-43 (TARDBP) have been linked mostly to ALS and FTLD (50). We first analyzed 15 of these TDP-43 mutants with regard to ubiquitination and UBE2E3 responsiveness in transiently transfected HEK293E cells.…”

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

“…In addition to C9orf72 and SOD1, genes considered as 'major' ALS-causing genes are TAR DNA binding protein (TARDBP) [27][28][29] and fused in sarcoma (FUS) [30,31], which account for about 3% of FALS and 1.5% of SALS, and 5% of FALS and 1% of SALS, respectively. These mutations have been validated by a multitude of studies, with patients from different geographic origins (reviewed in [32]). Both TDP-43 (encoded by TARDBP) and FUS contain RNA-binding domains and have an important role in RNA processing, suggesting that dysfunction in RNA metabolism is involved in ALS pathogenesis (reviewed in [33]).…”

The genetic basis of amyotrophic lateral sclerosis: recent breakthroughs

“…71 To this day, up to 47 missense mutations and one truncated variant have been identified. 72 Nearly all of the missense mutations reside in exon 6, which encodes the C-terminal glycine-rich part. 73 TARDBP mutations have been reported in 4% of FALS and 1% of SALS cases.…”