title: Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease.
abstract: Nasu-Hakola disease (NHD) is a form of presenile dementia associated with sclerosing leukoencephalopathy and polycystic lipomembranous osteodysplasia. This extremely rare inherited disease is caused by mutations in either DAP12 or TREM2. The present study was designed to assess the relationship between DAP12/TREM2 genotype, mRNA and protein expression levels by both Western blotting and immunohistochemistry, and the tissue distribution and pathomorphological phenotype of the microglia. Molecular genetic testing performed in three NHD cases confirmed that two cases had mutations in DAP12 and that one case carried a mutation in TREM2. Protein levels were analyzed in four cases. Interestingly, significant DAP12 expression was found in numerous microglia in one NHD case with a homozygous DAP12 single-base substitution, and both real-time PCR and Western blotting confirmed the finding. In contrast, levels of both DAP12 and TREM2, respectively, were much lower in the other cases. Immunohistochemistry using established microglial markers revealed consistently mild activation of microglia in the cerebral white matter although there was no or only little expression of DAP12 in three of the NHD cases. The highly different expression of DAP12 represents the first description of such variable expressivity in NHD microglia. It raises important questions regarding the mechanisms underlying dementia and white matter damage in NHD.
authors.affiliation: Department of Pathology, Saitama Medical University, 38 Morohongo, Iruma, Saitama, 350-0495, Japan. asasaki@saitama-med.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Neurology Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Konno
authors.affiliation: Department of Molecular Genetics Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.affiliation: Department of Neurology, Mishima Hospital, Niigata, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Matsuo
authors.affiliation: Department of Pathology, Saitama Medical University, 38 Morohongo, Iruma, Saitama, 350-0495, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Shioda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001921:Brain / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008060:Lipodystrophy / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D010009:Osteochondrodysplasias / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics*; D013344:Subacute Sclerosing Panencephalitis / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C110546:TYROBP protein, human
keywords: DAP12; Macrophage; Microglia; Nasu-Hakola disease; PLOSL; TREM2