Pekkarinen P, Kestilä M, Paloneva J, Terwillign J, Varilo T, Järvi O, Hakola P, Peltonen L
National Public Health Institute and Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Genomics. 1998 Dec 1;54(2):307-15. doi: 10.1006/geno.1998.5591.
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.
伴有硬化性白质脑病的多囊性脂膜性骨发育异常（PLOSL；MIM 221770）是早老性痴呆的一种罕见遗传病因，呈常染色体隐性遗传。其独特特征是伴有痴呆的囊性骨病变。迄今为止已报道约160例，大多在芬兰和日本。PLOSL的病因和发病机制尚不清楚。我们最近在芬兰人群中将PLOSL的基因座定位于19号染色体q13.1（P. Pekkarinen等人，1998年，《美国人类遗传学杂志》62卷，362 - 272页）。在本研究中，我们通过连锁不平衡定位将PLOSL的关键区域限定在153 kb。首先，在PLOSL关键区域发现了三个新的微卫星标记。在芬兰的PLOSL家系中分析了这些标记以及跨越关键区域的其他三个标记。在这些标记与PLOSL之间检测到强连锁不平衡（多点P值<10^(-47)），对于两个标记D19S1176和D19S610，所有PLOSL染色体分别共享相同的171和218 bp等位基因。单倍型分析揭示了芬兰PLOSL染色体中有五种不同的单倍型。但它们都共享标记D19S1175和D19S608之间的区域，该区域可通过单一重组事件追溯到一个祖先单倍型，从而将关键区域定义为153 kb。多点关联分析还将PLOSL基因座在该区间内最可能的位置定位于标记D19S610的紧邻区域。通过测序研究了一个有希望的PLOSL位置候选基因，一种淀粉样前体样蛋白，但未检测到突变。这些结果为克隆这个新的痴呆基因以及在芬兰人群中使用单倍型分析进行诊断奠定了基础。
