Assignment of the Locus for PLO-SL, a Frontal-Lobe Dementia with Bone Cysts, to 19q13

Department of Human Molecular Genetics, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/1998; 62(2):362-72. DOI: 10.1086/301722
Source: PubMed


PLO-SL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile frontal-lobe dementia, resulting in death at <50 years of age. Since the 1960s, approximately 160 cases have been reported, mainly in Japan and Finland. The pathogenesis of the disease is unknown. In this article, we report the assignment of the locus for PLO-SL, by random genome screening using a modification of the haplotype-sharing method, in patients from a genetically isolated population. By screening five patient samples from 2 Finnish families, followed by linkage analysis of 12 Finnish families, 3 Swedish families, and 1 Norwegian family, we were able to assign the PLO-SL locus to a 9-cM interval between markers D19S191 and D19S420 on chromosome 19q13. The critical region was further restricted, to approximately 1.8 Mb, by linkage-disequilibrium analysis of the Finnish families. According to the haplotype analysis, one Swedish and one Norwegian PLO-SL family are not linked to the chromosome 19 locus, suggesting that PLO-SL is a heterogeneous disease. In this chromosomal region, one potential candidate gene for PLO-SL, the gene encoding amyloid precursor-like protein 1, was analyzed, but no mutations were detected in the coding region.

Download full-text


Available from: Petra Ijäs
  • Source
    • "Genotyping was performed as described elsewhere (Wessman et al. 2002). The genotyped families originated from Sweden (Nylander et al. 1996) and Norway (Edvardsen et al. 1983), and each had two affected family members (Pekkarinen et al. 1998a; Paloneva et al. 2000). The only chromosomal region showing complete cosegregation with PLOSL was the 6p21-p22 region covered by the markers D6S1616, D6S1575, and D6S1549 (fig. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as "Nasu-Hakola disease," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype.
    Preview · Article · Oct 2002 · The American Journal of Human Genetics
  • Source
    • "DNA samples were extracted, from 20-ml EDTA blood, according to a standard procedure (Blin and Stafford 1976) modified to adapt Phase Lock Gel tubes (5 r 3 ). PCR amplification and gel electrophoresis performed with the use of either the automated DNA sequencer or radioactivity have been described elsewhere (Pekkarinen et al. 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Here, we report the results from a three-stage genomewide screen performed in a study sample from an internal isolate of Finland. An effort was made to identify genes predisposing for schizophrenia that are potentially enriched in this isolate, which has an exceptionally high lifetime risk for this trait. Ancestors of the local families with schizophrenia were traced back to the foundation of the population in the 17th century. This genealogical information was used as the basis for the study strategy, which involved screening for alleles shared among affected individuals originating from common ancestors. We found four chromosomal regions with markers revealing pairwise LOD scores>1.0: 1q32.2-q41 (Z(max)=3.82, dominant affecteds-only model), 4q31 (Z(max)=2. 74, dominant 90%-penetrance model), 9q21 (Z(max)=1.95, dominant 90%-penetrance model), and Xp11.4-p11.3 (Z(max)=2.01, recessive 90%-penetrance model). This finding suggests that there are several putative loci predisposing to schizophrenia, even in this isolate.
    Full-text · Article · Oct 1999 · The American Journal of Human Genetics
  • Source
    • "Thus it seemed a very interesting positional candidate for the PLOSL gene. The exonic sequences of APLP1 have been studied by SSCP (Pekkarinen et al., 1998) and sequencing (this study), but no mutations were identified in the PLOSL patients , and thus it can be concluded that mutations in the coding region of this gene do not cause PLOSL. A novel gene, NPHS1, coding for a glomerular protein, nephrin, was recently reported to reside on 19q13.1 and to be mutated in congenital nephrotic syndrome of the Finnish type (Kestilä et al., 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770) is a rare hereditary cause of presenile dementia with autosomal recessive inheritance. Its unique feature is the cystic bone lesions that accompany the dementia. About 160 cases have been reported to date, mostly in Finland and Japan. The etiology and pathogenesis of PLOSL are unknown. We recently assigned the locus for PLOSL in the Finnish population to chromosome 19q13.1 (P. Pekkarinen et al., 1998, Am. J. Hum. Genet. 62, 362-272). In the present study, we restrict the critical region for PLOSL to 153 kb by linkage-disequilibrium mapping. First, three new microsatellite markers were revealed in the PLOSL critical region. These and three other markers spanning the critical region were analyzed in Finnish PLOSL families. Strong linkage disequilibrium (multipoint P value < 10(-47)) was detected between the markers and PLOSL, and for two markers, D19S1176 and D19S610, all the PLOSL chromosomes shared identical 171- and 218-bp alleles, respectively. Haplotype analysis revealed five different haplotypes in the Finnish PLOSL chromosomes. But all of them shared the region between markers D19S1175 and D19S608 that could be traced to one ancestor haplotype by single recombination events, thus defining the critical region as 153 kb. Multipoint association analysis also assigned the most likely location of the PLOSL locus within this interval to the immediate vicinity of marker D19S610. A promising positional candidate for PLOSL, an amyloid precursor-like protein, was studied by sequencing, but no mutations were detected. These results lay the basis for the cloning of this novel dementia gene and for diagnostics in the Finnish population using haplotype analysis.
    Full-text · Article · Jan 1999 · Genomics
Show more