Fine-scale mapping of a novel dementia gene, PLOSL, by linkage disequilibrium

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopath y (PLOSL; MIM 221770) is a rare hereditary cause of presenile dementia with autosomal recessive inheritance. Its unique feature is the cystic bone les ions that accompany the dementia About 160 cases have been reported to date , mostly in Finland and Japan The etiology and pathogenesis of PLOSL are un known We recently assigned the locus for PLOSL in the Finnish population to chromosome 19q13.1 (P. Pekkarinen ct at, 1998, Am. J. Hum. Genet. 62, 362- 272). In the present study, we restrict the critical region for PLOSL to 15 3 kb by linkage-disequilibrium mapping. First, three new microsatellite mar kers were revealed in the PLOSL critical region. These and three other mark ers spanning the critical region were analyzed in Finnish PLOSL families. S trong linkage disequilibrium (multipoint P value < 10(-47)) was detected be tween the markers and PLOSL, and for two markers, D19S1176 and D19S610, all the PLOSL chromosomes shared identical 171- and 218-bp alleles, respective ly. Haplotype analysis revealed five different haplotypes in the Finnish PL OSL chromosomes. But all of them shared the region between markers D19S1175 and D19S608 that could be traced to one ancestor haplotype by single recom bination events, thus defining the critical region as 153 kb. Multipoint as sociation analysis also assigned the most likely location of the PLOSL locu s within this interval to the immediate vicinity of marker D19S610. A promi sing positional candidate for PLOSL, an amyloid precursor-like protein, was studied by sequencing, but no mutations were detected. These results lay t he basis for the cloning of this novel dementia gene and for diagnostics in the Finnish population using haplotype analysis. (C) 1998 Academic Press.