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

  title={Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts},
  author={Juha Paloneva and Marjo Kestilä and Jun Wu and Antti Salminen and Tom B{\"o}hling and Vesa Ruotsalainen and Panu Hakola and Alexander Berthold Hendrik Bakker and Joseph H. Phillips and Petra Pekkarinen and Lewis L. Lanier and Tuomo T Timonen and Leena Peltonen},
  journal={Nature Genetics},
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 2×10−6 (ref. 2) in the Finns. We have… 

Heterozygous TYROBP deletion (PLOSLFIN) is not a strong risk factor for cognitive impairment

The C9ORF72 expansion does not affect the phenotype in Nasu-Hakola disease with the DAP12 mutation

Nasu–Hakola Disease (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy—PLOSL): A Dementia Associated with Bone Cystic Lesions. From Clinical to Genetic and Molecular Aspects

The authors review the clinical, radiological, electrophysiological, pathological, and molecular aspects of Nasu–Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing

Identification of the Meckel syndrome gene (MKS1) exposes a novel ciliopathy

This study identified the first MKS gene by utilizing the disease haplotypes in Finnish MKS families linked to the MKS1 locus on chromosome 17q23 (MKS1) locus and found three different MKS mutations, one of them being the Finnish founder mutation.

The TREM2-DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective

The genetic causes of PLOSL with loss-of-function mutations or deletions in one of two genes, TYROBP and TREM2, encoding for two proteins DNAX-activating protein 12 (DAP12) and triggering receptor expressed on myeloid cells-2 (TREM2).

An Italian family with Nasu-Hakola disease

An Italian family with Nasu-Hakola disease with 4 siblings born from non-consanguineous parents from Piedmont, with rapid global deterioration of mental status took place, in the absence of pains in bones or joints and of minimal fractures from trauma.

Mutations in the colony stimulating factor 1 receptor (CSF1R) cause hereditary diffuse leukoencephalopathy with spheroids

It is suggested that HDLS may result from partial loss of CSF1R function, and an important role for microglial dysfunction in HDLS pathogenesis is suggested.

Heterogeneity of presenile dementia with bone cysts (Nasu–Hakola disease):: Three genetic forms

Japanese NHD has at least three genetic forms regarding DAP12, with five of the six cases having loss-of-function mutation, either a single-base deletion or a novel point mutation.

Phenotypic Expansion in Nasu-Hakola Disease: Immunological Findings in Three Patients and Proposal of a Unifying Pathogenic Hypothesis

Findings tend to redefine NHD as a multisystem “immunological” disease, considering that osteoclasts are derived from the fusion of mononuclear myeloid precursors, whereas neurological anomalies in NHD are directly caused by microglia dysfunction.



Fine-scale mapping of a novel dementia gene, PLOSL, by linkage disequilibrium.

The critical region for PLOSL is restricted to 153 kb by linkage-disequilibrium mapping to lay the basis for the cloning of this novel dementia gene and for diagnostics in the Finnish population using haplotype analysis.

Assignment of the locus for PLO-SL, a frontal-lobe dementia with bone cysts, to 19q13.

The assignment of the locus for PLO-SL, by random genome screening using a modification of the haplotype-sharing method, in patients from a genetically isolated population is reported, suggesting that PLo-SL is a heterogeneous disease.

Nasu-Hakola syndrome: polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy and presenile dementia.

Nasu-Hakola syndrome is reviewed, another unusual cause of presenile intellectual deterioration, in which neurological impairment occurs together with impressive destructive changes of the skeleton.

Structure of the human amyloid-precursor-like protein gene APLP1 at 19q13.1

No differences were observed between CNF patients and controls, suggesting that mutations in APLP1 are not involved in the etiology of CNF, suggesting the gene for congenital nephrotic syndrome is a candidate gene for CNF.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLO‐SL): a genealogical study of Swedish families of probable Finnish background

Four Swedish families in northern Sweden with polycystic lipomembranous ostodysplasia (PLO‐SL) were studied genealogically. Historical and genealogical data provided evidence for a Finnish origin.

Vascular changes and blood‐brain barrier damage in the pathogenesis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (membranous lipodystrophy)

It is proposed that severe chronic vasogenic brain edema is the main pathogenetic mechanism of the severe leukoencephalopathy in this disease entity.

Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia.

  • H. Hakola
  • Medicine
    Acta psychiatrica Scandinavica. Supplementum
  • 1972
A new book enPDFd neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia that can be a new way to explore the knowledge is shown.

Molecular genetics of the Finnish disease heritage.

Identification of mutated genes has provided tools for detailed analyses of molecular pathogenesis in Finnish diseases, many of which reveal a distinct tissue specificity of clinical phenotype, often providing novel information on biological processes and metabolic pathways essential for normal development and function of human cells and tissues.

Cutting edge: KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties.

A novel transmembrane adapter protein called KAP10, a approximately 10-kDa protein that is encoded within 100 bp of the DAP12 locus on human chromosome 19 is cloned and it is suggested that this molecule is involved in stimulation and costimulation in cells of both myeloid and lymphoid origin.