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.
Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy--PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects.
In the systematic review, 12 biallelic TREM2 mutations (e.g., rs104894002, rs201258663 (rs201258663" genes_norm="54209">T66M), and rs386834144, etc.) have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) in 14 families.
In this paper, we have studied polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), an early onset dementia with bone fractures caused by mutations in TYROBP (DAP12) and TREM2 genes, which encode important signaling molecules in human dendritic cells (DCs).
We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG.
Plasma membrane receptors play primary roles as activators of microglia and in this review, we focus on a receptor complex involving triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), both of which are causative genes for Nasu-Hakola disease, a dementia with bone cysts.
The disease PLOSL and the finding that TREM2 of microglia is required for tissue debris clearance provide prototypic molecular evidence that dysfunctional innate immunity can be disease causative leading to a chronic neurodegenerative process.
In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL).
We found a previously unreported compound heterozygous mutation in TREM2, that is commonly associated with the recessively inherited Nasu-Hakola disease.