Year: 2003
Type: dissertation
Study design: Observational Study
Abstract: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease, is a monogenic model for dementia.It is characterized by loss of white matter in the brain, cystic bone lesions, and osteoporotic features, leading to severe dementia and spontaneous bone fractures.PLOSL has an autosomal recessive mode of inheritance.The incidence of the disease is highest in Finland and PLOSL therefore belongs to the Finnish disease heritage.When this study was started in 1998, the locus for PLOSL in Finnish patients had been restricted to a 153 kb region in chromosome 19q13.1.In this study we have used the positional cloning approach to identify the first gene mutated in PLOSL.We identified a homozygous 5.3 kb genomic deletion in all Finnish PLOSL patients in the DAP12 gene.DAP12 is a widely expressed transmembrane adaptor molecule that transmits activating signals from several cell-surface receptors that activate immune responses in myeloid and natural killer cells.We did not detect mutations in a group of patients outside Finland.This observation suggested genetic heterogeneity in PLOSL, and encouraged us to search for other PLOSL genes.Since DAP12 encodes a cell-surface receptor element that interacts with many different proteins depending on the cell type, we used a genetic approach to search for genes involved in PLOSL.By analyzing families not linked to DAP12 for segregation of marker haplotypes flanking genes coding for the DAP12-associated polypeptides, we identified a single chromosomal region that showed a complete cosegregation with PLOSL.Sequencing of the regional candidate genes revealed mutations in TREM2.On the cell surface TREM2 is expressed as a complex with DAP12 and mediates the differentiation of dendritic cells.
Source: Työväentutkimus Vuosikirja
Author: Juha Paloneva
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W597728022