Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
van der Zee J, Van Langenhove T, Kovacs GG, Dillen L, Deschamps W, Engelborghs S, Matěj R, Vandenbulcke M et al.. Acta neuropathologica, 2014-06-05
Topic: Brain proteins, microglia and lab models
Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
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APA 7th
van der Zee, J., Van Langenhove, T., Kovacs, G. G., Dillen, L., Deschamps, W., Engelborghs, S., et al. (2014). Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration. Acta neuropathologica. https://doi.org/10.1007/s00401-014-1298-7
Vancouver
van der Zee J, Van Langenhove T, Kovacs GG, Dillen L, Deschamps W, Engelborghs S, et al. Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration. Acta neuropathologica. 2014. doi:10.1007/s00401-014-1298-7. PMID: 24899140.
BibTeX
@article{vanderzee2014-24899140,
author = {van der Zee, J. and Van Langenhove, T. and Kovacs, G. G. and Dillen, L. and Deschamps, W. and Engelborghs, S. and Matěj, R. and Vandenbulcke, M. and others},
title = {{Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration}},
journal = {Acta neuropathologica},
year = {2014},
doi = {10.1007/s00401-014-1298-7},
pmid = {24899140},
url = {https://doi.org/10.1007/s00401-014-1298-7}
}
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Key findings
- Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone.
- When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients.
- Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042).
- Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology.
- With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
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Study details
- Study designmeta-analysis
- Participants3,899
- Effect sizeRR = 2.18
- Evidence strengthHigh
How this study scored 86/100
Published in a leading specialty journal, and it is a meta-analysis pooling many studies. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 50 of the 58 points we could judge it on, which is 86 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2014 — within 20 year(s) of the newest study here |
| Sample size | 3 / 4 | 3,899 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 24899140) |
| Free to read | 2 / 2 | Free to read |
| Points | 50 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 50 of the 58 points we could judge it on is 86 out of 100. |
| Total | 86 / 100 | — |
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