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

Nasu-Hakola disease (NHD) is a rare autosomal recessive disease that is characterized by cyst-like bone lesions and pathologic fractures combined with an early-onset frontal type of dementia. Mutations in DNAX-activation protein 12 (DAP12) and triggering receptor expressed on myeloid cells 2 (TREM2) are the known genetic causes of NHD. However, the role of both these genes in the neurodegenerative process is still partly unclear, and the input of other modifying factors has been postulated. Frontotemporal lobar degeneration (FTLD) is a neuropathologically and genetically heterogeneous neurodegenerative disease. A hexanucleotide repeat expansion in the chromosome 9-associated open reading frame 72 (C9ORF72) gene is the most common cause of familial FTLD in Finland. Here, we describe a family with 3 siblings with a clinical diagnosis of NHD. All patients had an equivalent age of onset of the behavioral/cognitive symptoms, and brain imaging revealed a similar pattern of brain atrophy and calcification in putamen and caudate nucleus. Case II-3 had the most severe phenotype with epilepsy and a rapid cognitive decline. Genetic analyses were performed in 2 patients (cases II-2 and II-3), and both had a homozygous DAP12 deletion. Because the role of DAP12 and TREM2 in neurodegeneration in NHD is partly unclear, our aim was to evaluate the role of other genetic variations as modifiers. The C9ORF72 expansion was found in case II-2. Exome sequencing did not reveal any other mutations that could be involved in FTLD. Case II-3 had a novel predictably deleterious mutation in the progressive myoclonic epilepsy type 2 (EPM2), which may have influenced his epilepsy as the EPM2 has been implicated in Lafora progressive myoclonic epilepsy. We conclude that the C9ORF72 expansion is probably an incidental finding because it did not have any apparent influence on the phenotype. Exome sequencing identified several rare missense variants and indels. Additional analyses in other NHD patients will be needed to elucidate their clinical relevance.

Word list learning in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy.

BACKGROUND/AIMS: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a rare hereditary disease that is characterized by a combination of progressive presenile dementia and sclerosing leukoencephalopathy with bone cysts. No quantitative information on verbal memory functioning in PLOSL patients compared with control subjects is available. METHODS: 23 patients with PLOSL and 23 control subjects were examined with a version of the 10-word list-learning task. Learning curves were compared between the patients and the matched control subjects. RESULTS: Compared with the control subjects, PLOSL patients with moderate or severe dementia were impaired in both learning trials and delayed recall on the 10-word list-learning test. CONCLUSION: Progressive degeneration of brain structures affecting the hippocampus and the medial temporal lobe with advanced PLOSL disease contributes to an inefficient verbal learning process.

Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response.

Rare monogenic dementias have repeatedly exposed novel pathways guiding to details of the molecular pathogenesis behind this complex clinical phenotype. 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). To identify the pathways and biological processes associated with DAP12/TREM2-mediated signaling, we performed genome wide transcript analysis of in vitro differentiated DCs of PLOSL patients representing functional knockouts of either DAP12 or TREM2. Both DAP12- and TREM2-deficient cells differentiated into DCs and responded to pathogenic stimuli. However, the DCs showed morphological differences compared to control cells due to defects in the actin filaments. Not unexpectedly, transcript profiles of the patient DCs showed differential expression of genes involved in immune response. Importantly, significantly diverging transcript levels were also evident for genes earlier associated with other disorders of the central nervous system (CNS) and genes involved in the remodeling of bone, linking these two immunological genes with critical tissue phenotypes of patients. The data underline the functional diversity of the molecules of the innate immune system and implies their significant contribution also in demyelinating CNS disorders, including those resulting in dementia.

DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), Nasu-Hakola disease, is a globally distributed recessively inherited disease. PLOSL is characterized by cystic bone lesions, osteoporotic features, and loss of white matter in the brain leading to spontaneous bone fractures and profound presenile dementia. We have earlier characterized the molecular genetic background of PLOSL by identifying mutations in two genes, DAP12 and TREM2. DAP12 is a transmembrane adaptor protein that associates with the cell surface receptor TREM2. The DAP12-TREM2 complex is involved in the maturation of dendritic cells. To test a hypothesis that osteoclasts would be the cell type responsible for the bone pathogenesis in PLOSL, we analyzed the differentiation of peripheral blood mononuclear cells isolated from DAP12- and TREM2-deficient PLOSL patients into osteoclasts. Here we show that loss of function mutations in DAP12 and TREM2 result in an inefficient and delayed differentiation of osteoclasts with a remarkably reduced bone resorption capability in vitro. These results indicate an important role for DAP12-TREM2 signaling complex in the differentiation and function of osteoclasts.