Home › Research › Lewy body dementia
Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements
D'Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, Schellenberg GD.. Proceedings of the National Academy of Sciences of the United States of America, 1999-05-01
Topic: Brain proteins, microglia and lab models
Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17) is caused by mutations in the tau gene, and the signature lesions of FTDP-17 are filamentous tau inclusions. Tau mutations may be pathogenic either by altering protein function or gene regulation. Here we show that missense, silent, and intronic tau mutations can increase or decrease splicing of tau exon 10 (E10) by acting on 3 different cis-acting regulatory elements. These elements include an exon splicing enhancer that can either be strengthened (mutation N279(K)) or destroyed (mutation Delta280(K)), resulting in either constitutive E10 inclusion or the exclusion of E10 from tau transcripts. E10 contains a second regulatory element that is an exon splicing silencer, the function of which is abolished by a silent FTDP-17 mutation (L284(L)), resulting in excess E10 inclusion. A third element inhibiting E10 splicing is contained in the intronic sequences directly flanking the 5' splice site of E10 and intronic FTDP-17 mutations in this element enhance E10 inclusion. Thus, tau mutations cause FTDP-17 by multiple pathological mechanisms, which may explain the phenotypic heterogeneity observed in FTDP-17, as exemplified by an unusual family described here with tau pathology as well as amyloid and neuritic plaques.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
D'Souza, I., Poorkaj, P., Hong, M., Nochlin, D., Lee, V. M., Bird, T. D., et al. (1999). Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.96.10.5598
Vancouver
D'Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, et al. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proceedings of the National Academy of Sciences of the United States of America. 1999. doi:10.1073/pnas.96.10.5598. PMID: 10318930.
BibTeX
@article{dsouza1999-10318930,
author = {D'Souza, I. and Poorkaj, P. and Hong, M. and Nochlin, D. and Lee, V. M. and Bird, T. D. and Schellenberg, G. D.},
title = {{Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {1999},
doi = {10.1073/pnas.96.10.5598},
pmid = {10318930},
url = {https://doi.org/10.1073/pnas.96.10.5598}
}
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 names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- Here we show that missense, silent, and intronic tau mutations can increase or decrease splicing of tau exon 10 (E10) by acting on 3 different cis-acting regulatory elements.
- These elements include an exon splicing enhancer that can either be strengthened (mutation N279(K)) or destroyed (mutation Delta280(K)), resulting in either constitutive E10 inclusion or the exclusion of E10 from tau transcripts.
- E10 contains a second regulatory element that is an exon splicing silencer, the function of which is abolished by a silent FTDP-17 mutation (L284(L)), resulting in excess E10 inclusion.
- A third element inhibiting E10 splicing is contained in the intronic sequences directly flanking the 5' splice site of E10 and intronic FTDP-17 mutations in this element enhance E10 inclusion.
- Thus, tau mutations cause FTDP-17 by multiple pathological mechanisms, which may explain the phenotypic heterogeneity observed in FTDP-17, as exemplified by an unusual family described here with tau pathology as well as amyloid and neuritic plaques.
Why it matters
This laboratory work showed that different tau mutations can increase or decrease inclusion of tau exon 10 by acting on three regulatory elements. It explains one way a tau mutation may cause disease but does not test any treatment, cure or prevention.
Study details
- Evidence strengthLow
How this study scored 51/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Proceedings of the National Academy of Sciences of the United States of America) |
| Journal's citation record | 4 / 4 | Proceedings of the National Academy of Sciences: journal h-index 1,167 (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 | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 1999 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 518 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 17.9 citations a year over 29 year(s) since 1999 |
| Impact for its field and year | 5 / 6 | Cited 25.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 14 other studies in this library |
| Still being cited | 2 / 4 | Cited 23 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Gerard D. Schellenberg: h-index 94 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 10318930) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 51 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 14.
Later studies that cite this one
14 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.
Related studies in Lewy body dementia
Also tagged “phosphorylated”
732 studies in the library carry the topic tag “phosphorylated”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 732 tagged studies.