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Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts

Nature Genetics volume 25, pages 357–361 (2000)Cite this article

Abstract

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 ankles1,2,3. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland4 and Japan, with an estimated population prevalence of 2×10−6 (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 protein7 (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells8. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules7,9. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

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Figure 1: TYROBP and DAP10, located in opposite transcriptional orientation on chromosome 19q13.1, and identified PLOSL mutations in TYROBP.
Figure 2: Northern (a) and western (b) analysis of TYROBP and DAP10 transcripts and corresponding polypeptides of patients carrying PLOSLFin mutations.
Figure 3: Northern-blot analysis of TYROBP in multiple human tissues.

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Acknowledgements

We thank R. Machinami for the tissue sample from the Japanese PLOSL patient. This work was supported by The Academy of Finland, Sigrid Jusélius Foundation, Hjelt Fond of the Pediatric Research Foundation and Helsinki University Central Hospital. Schering Plough Corporation supported DNAX Research Institute. The Sandler Family Supporting Foundation funded studies at University of California San Francisco.

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Authors and Affiliations

  1. Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland

    Juha Paloneva, Petra Pekkarinen & Leena Peltonen

  2. Department of Human Genetics, UCLA School of Medicine, Gonda Center, University of California Los Angeles, Los Angeles, California, USA

    Juha Paloneva & Leena Peltonen

  3. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland

    Marjo Kestilä

  4. Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland

    Antti Salminen, Tom Böhling & Tuomo Timonen

  5. Department of Microbiology and Immunology and the Cancer Research Center, University of California San Francisco, San Francisco, California, USA

    Jun Wu, Alexander B.H. Bakker & Lewis L. Lanier

  6. Department of Biochemistry and Biocenter Oulu, Oulu, Finland

    Vesa Ruotsalainen

  7. Department of Forensic Psychiatry, University of Kuopio, Kuopio, Finland

    Panu Hakola

  8. Immunobiology Department, DNAX Research Institute, Palo Alto, California, USA

    Joseph H. Phillips

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  1. Juha Paloneva
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Correspondence to Leena Peltonen.

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Paloneva, J., Kestilä, M., Wu, J. et al. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25, 357–361 (2000). https://doi.org/10.1038/77153

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