Genetic contribution of FUS to frontotemporal lobar degeneration.
BACKGROUND
Recently, the FUS gene was identified as a new causal gene for amyotrophic lateral sclerosis (ALS) in approximately 4% of patients with familial ALS. Since ALS and frontotemporal lobar degeneration (FTLD) are part of a clinical, pathologic, and genetic disease spectrum, we investigated a potential role of FUS in FTLD.


METHODS
We performed mutational analysis of FUS in 122 patients with FTLD and 15 patients with FTLD-ALS, as well as in 47 patients with ALS. Mutation screening was performed by sequencing of PCR amplicons of the 15 FUS exons.


RESULTS
We identified 1 patient with FTLD with a novel missense mutation, M254V, that was absent in 638 control individuals. In silico analysis predicted this amino acid substitution to be pathogenic. The patient did not have a proven family history of neurodegenerative brain disease. Further, we observed the known R521H mutation in 1 patient with ALS. No FUS mutations were detected in the patients with FTLD-ALS. While insertions/deletions of 2 glycines (G) were suggested to be pathogenic in the initial FUS reports, we observed an identical GG-deletion in 2 healthy individuals and similar G-insertions/deletions in 4 other control individuals, suggesting that G-insertions/deletions within this G-rich region may be tolerated.


CONCLUSIONS
In a first analysis of FUS in patients with frontotemporal lobar degeneration (FTLD), we identified a novel FUS missense mutation, M254V, in 1 patient with pure FTLD. At this point, the biologic relevance of this mutation remains elusive. Screening of additional FTLD patient cohorts will be needed to further elucidate the contribution of FUS mutations to FTLD pathogenesis.
Van Langenhove
T
T
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp-CDE, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
van der Zee
J
J
Sleegers
K
K
Engelborghs
S
S
Vandenberghe
R
R
Gijselinck
I
I
Van den Broeck
M
M
Mattheijssens
M
M
Peeters
K
K
De Deyn
P P
PP
Cruts
M
M
Van Broeckhoven
C
C
D000368:Aged; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D016415:Sequence Alignment; D017384:Sequence Deletion; D014633:Valine / Q000235:genetics
D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; D008715:Methionine; D014633:Valine; D005998:Glycine