Transcriptome analysis of the Nasu-Hakola disease brain

Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; OMIM 221770), is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of DAP12 and TREM2, which constitute a receptor/adapter signaling complex expressed on osteoclasts, dendritic cells, macrophages, and microglia. No Japanese patients with TREM2 mutations have been reported previously. We reported three siblings affected with NHD in a Japanese family. Among them, two died of NHD during the fourth decade of life. The transcriptome was studied in the autopsized brain of one patient. We found a homozygous conversion of a single nucleotide T to C at the second position of intron 3 in the splice-donor consensus site (c.482+2T>C) of the TREM2 gene, resulting in exon 3 skipping. We identified 136 upregulated genes involved in inflammatory response and immune cell trafficking and 188 downregulated genes including a battery of GABA receptor subunits and synaptic proteins in the patients brain.

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Numasawa Y, Yamaura C, Ishihara S, Shintani S, Yamazaki M, Tabunoki H, Satoh JI