TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations.
OBJECTIVE
Increasing evidence suggests a direct role of the TAR DNA-binding protein 43 (TDP-43) in neurodegeneration. Mutations in the TARDBP gene, which codes for TDP-43, have been recently reported in familial and sporadic amyotrophic lateral sclerosis (ALS) cases.


METHODS
To further define the spectrum and frequency of TARDBP mutations, we present genetic analysis data on TARDBP in 314 ALS mainly Italian patients, including 16 subjects with non-SOD1 familial ALS.


RESULTS
We identified four heterozygous missense mutations in five unrelated ALS patients (1.6%). Two of these mutations (p.G348C and p.A382T) were detected in carriers coming from families with an autosomal dominant transmission of different geographic origin (Belgian and Italian, respectively). The Belgian pedigree showed several affected members within five generations and with variable clinical features. Two novel mutations (p.G294V and p.G295S) were identified in two sporadic cases.


CONCLUSIONS
The identification of five ALS patients carrying TARDBP alterations extends the spectrum of TARDBP mutations and supports the pathological role of TDP-43 in motor neurone disease. Our findings provide evidence that TARDBP mutations are not frequent in Italian sporadic ALS patients (1%); however, combined with the literature, our data further support TARDBP mutations as a relevant cause of familial ALS.
Del Bo
R
R
Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, Milan, Italy. roberto.delbo@unimi.it
Ghezzi
S
S
Corti
S
S
Pandolfo
M
M
Ranieri
M
M
Santoro
D
D
Ghione
I
I
Prelle
A
A
Orsetti
V
V
Mancuso
M
M
Sorarù
G
G
Briani
C
C
Angelini
C
C
Siciliano
G
G
Bresolin
N
N
Comi
G P
GP
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001483:Base Sequence / Q000235:genetics; D001530:Belgium; D025063:Chromosome Disorders / Q000235:genetics; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree
D004268:DNA-Binding Proteins