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

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopath y (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapi dly progressing to presenile dementia and bone cysts restricted to wrists a nd ankles(1-3). PLOSL has a global distribution, although most of the patie nts have been diagnosed in Finland(4) and Japan. with an estimated populati on prevalence of 2x10(-6) (ref. 2) in the Finns. We have previously identif ied a shared 153-kb ancestor haplotype in all Finnish disease alleles betwe en markers D1951175 and D195608 on chromosome 19q13.1 (refs 5,6). Here we c haracterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, b oth representing loss-of-function mutations, in the gene encoding TYRO prot ein tyrosine kinase binding protein(7) (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells(8). On the plasma membra ne of NK cells, TYROBP associates with activating receptors recognizing maj or histocompatibility complex (MHC) class I molecules(7,9). No abnormalitie s in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.