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Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts
Paloneva J, Kestilä M, Wu J, Salminen A, Böhling T, Ruotsalainen V, Hakola P, Bakker AB et al.. Nature genetics, 2000-07-01
Topic: Brain proteins, microglia and lab models
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.
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APA 7th
Paloneva, J., Kestilä, M., Wu, J., Salminen, A., Böhling, T., Ruotsalainen, V., et al. (2000). Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nature genetics. https://doi.org/10.1038/77153
Vancouver
Paloneva J, Kestilä M, Wu J, Salminen A, Böhling T, Ruotsalainen V, et al. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nature genetics. 2000. doi:10.1038/77153. PMID: 10888890.
BibTeX
@article{paloneva2000-10888890,
author = {Paloneva, J. and Kestilä, M. and Wu, J. and Salminen, A. and Böhling, T. and Ruotsalainen, V. and Hakola, P. and Bakker, A. B. and others},
title = {{Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts}},
journal = {Nature genetics},
year = {2000},
doi = {10.1038/77153},
pmid = {10888890},
url = {https://doi.org/10.1038/77153}
}
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Key findings
- We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6).
- Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12).
- TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells.
- On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules.
- No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.
Why it matters
In Nasu-Hakola disease (PLOSL), a rare inherited condition of "psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles", this study found loss-of-function mutations in the TYROBP (DAP12) gene: "one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient". TYROBP was known as a signalling protein in immune NK cells, yet patients carrying two non-working copies showed "no abnormalities in NK cell function". The paper is about this rare disease only. It does not study Alzheimer's disease and does not test any treatment.
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Study details
- Evidence strengthLow
How this study scored 53/100
Published in a leading specialty 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 | 9 / 10 | Tier 2 — leading specialty journal (Nature genetics) |
| Journal's citation record | 4 / 4 | Nature Genetics: journal h-index 776 (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 | 2000 — 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 463 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 16.5 citations a year over 28 year(s) since 2000 |
| Impact for its field and year | 4 / 6 | Cited 9.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 71 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 | 3 / 4 | Last-listed author Leena Peltonen: h-index 57 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, Los Angeles: institution h-index 1,923 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 10888890) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
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