Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.
BACKGROUND
Abnormal neuronal inclusions composed of the transactivation response DNA-binding protein 43 (TDP-43) are characteristic neuropathologic lesions in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). This makes TARDBP, the gene encoding for TDP-43, a candidate for genetic screening in ALS.


OBJECTIVE
To investigate the presence and frequency of TARDBP mutations in ALS.


METHODS
Genetic analysis.


METHODS
Academic research.


METHODS
One hundred thirty-four patients with sporadic ALS, 31 patients with familial non-superoxide dismutase 1 gene (non-SOD1) (OMIM 147450) ALS, and 400 healthy control subjects.


METHODS
We identified 2 missense mutations (G348C and the novel N352S) in TARDBP in 2 small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment.


RESULTS
The mutations located in the C-terminus of TDP-43 were absent in 400 controls of white race/ethnicity. The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation, while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges.


CONCLUSIONS
Mutations in TARDBP are a rare cause of familial non-SOD1 ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.
Kühnlein
Peter
P
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany.
Sperfeld
Anne-Dorte
AD
Vanmassenhove
Ben
B
Van Deerlin
Vivianna
V
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
Kretzschmar
Hans A
HA
Ludolph
Albert C
AC
Neumann
Manuela
M
D000368:Aged; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree
D004268:DNA-Binding Proteins
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