Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis remains largely unknown. Susceptibility loci for Paget's disease of bone have been mapped to chromosome 6p21.3 (PDB1) and 18q21.1‐q22 (PDB2) in different pedigrees. We have identified a large pedigree of over 250 individuals with 49 informative individuals affected with Paget's disease of bone; 31 of whom are available for genotypic analysis. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Linkage analysis has been performed with markers at PDB1; these data show significant exclusion of linkage with log10 of the odds ratio (LOD) scores < −2 in this region. Linkage analysis of microsatellite markers from the PDB2 region has excluded linkage with this region, with a 30 cM exclusion region (LOD score < −2.0) centered on D18S42. These data confirm the genetic heterogeneity of Paget's disease of bone. Our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Paget's disease of bone lies elsewhere in the genome in the affected members of this pedigree and will be identified using a microsatellite genomewide scan followed by positional cloning.
佩吉特骨病是一种常见疾病,其特征包括骨痛、畸形、病理性骨折及骨肉瘤的发生率增加。遗传因素在佩吉特骨病的发病机制中起作用,但其分子基础尚不清楚。佩吉特骨病的易感位点已在不同家系中定位于6p21.3(PDB1)和18q21.1-q22(PDB2)染色体上。我们已经识别出一个超过250人的大家系,其中49名信息量丰富的个体受佩吉特骨病影响;其中31人可用于
基因型分析。该病在家系中以常染色体显性遗传,六十岁时有很高的外显率。我们对PDB1区域的标记进行了连锁分析,这些数据显示在该区域的连锁排除率显著,log10赔率比(LOD)分数小于−2。对PDB2区域微卫星标记的连锁分析也排除了与该区域的连锁,排除区域为30 cM(LOD分数小于−2.0),以D18S42为中心。这些数据确认了佩吉特骨病的遗传异质性。我们的假设是,一个与佩吉特骨病发病机制相关的新易感
基因位于该家系受影响个体的
基因组其他位置,并将通过微卫星全
基因组扫描和后续的定位克隆技术进行识别。