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Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis
Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ et al.. PLoS genetics, 2008-09-19
Topic: Brain proteins, microglia and lab models
Plain-language summary
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.
What this study adds
Evidence grade: Moderate
The record lists 296 participants. In a screen of 296 patients with TDP-43-related brain diseases, three TARDBP gene changes turned up only in familial ALS (3 of 92, 3.3%), not in 24 sporadic ALS or 180 other TDP-43 disease patients, and were absent from 825 controls. Reported effect size: 3.3%.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Rutherford, N. J., Zhang, Y. J., Baker, M., Gass, J. M., Finch, N. A., Xu, Y. F., et al. (2008). Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS genetics. https://doi.org/10.1371/journal.pgen.1000193
Vancouver
Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS genetics. 2008. doi:10.1371/journal.pgen.1000193. PMID: 18802454.
BibTeX
@article{rutherford2008-18802454,
author = {Rutherford, N. J. and Zhang, Y. J. and Baker, M. and Gass, J. M. and Finch, N. A. and Xu, Y. F. and Stewart, H. and Kelley, B. J. and others},
title = {{Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis}},
journal = {PLoS genetics},
year = {2008},
doi = {10.1371/journal.pgen.1000193},
pmid = {18802454},
url = {https://doi.org/10.1371/journal.pgen.1000193}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology.
- Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines.
- Our findings support TARDBP mutations as a cause of ALS.
Why it matters
In a screen of 296 patients with TDP-43-related brain diseases, three TARDBP gene changes turned up only in familial ALS (3 of 92, 3.3%), not in 24 sporadic ALS or 180 other TDP-43 disease patients, and were absent from 825 controls. Patient cell lines showed more caspase-cleaved TDP-43 fragments than controls, which the authors say "support TARDBP mutations as a cause of ALS"; the mechanism they propose is stated as speculation. This is ALS genetics, not a finding about Alzheimer's disease, and it tests no treatment.
Study details
- Participants296
- Effect size3.3%
- Evidence strengthModerate
How this study scored 65/100
Published in a peer-reviewed journal. Scored zero for study design and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (PLoS genetics) |
| Journal's citation record | 3 / 4 | PLoS Genetics: journal h-index 341 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2008 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 296 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 458 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 22.9 citations a year over 20 year(s) since 2008 |
| Impact for its field and year | 5 / 6 | Cited 25.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 30 other studies in this library |
| Still being cited | 2 / 4 | Cited 37 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Rosa Rademakers: h-index 119 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, Los Angeles: institution h-index 1,923 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 11 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 18802454) |
| Free to read | 2 / 2 | Free to read |
| Total | 65 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1371/journal.pgen.1000193
- PubMed: 18802454
- Original source →
- Free full text: PLoS Genetics →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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