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 1, 2, 3. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland 4 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 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 membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules 7, 9. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.