FUS

Abstract

Following hard on the heels of discoveries of pathogenic mutations in the TAR DNA-binding protein 43 gene ( TDP-43/TARDBP ) in familial amyotrophic lateral sclerosis (FALS)1,2 and, less frequently, in frontotemporal lobar degeneration (FTLD),3,4 mutations in the fused in sarcoma/translocation in liposarcoma gene ( FUS/TLS ) were recently identified as causing about 4% of FALS.5,6 Some FALS cases had previously been linked to chromosome 16, which prompted Vance et al.5 and Kwiatkowski et al.6 to target genes encoding DNA/RNA-binding proteins within the linkage region; this resulted in independent identification of 15 different FUS mutations in 26 unrelated persons with FALS. Most of the mutations clustered in the C-terminal region of the protein encoded by exons 14 and 15. Interestingly, most of the reported pathogenic mutations in TARDBP are also within the C-terminal, glycine-rich domain. This clustering in a highly conserved region indicates that this region has functional significance and may be related to its role in binding heterogeneous nuclear ribonucleoproteins. Neuropathologic studies of TDP-43 proteinopathy place most sporadic and familial cases of ALS within a spectrum of disorders which includes ALS, FTLD, and cases with clinical and neuropathologic features of both (ALS-FTLD).7,8 More than half …