Genomewide search in familial Paget disease of bone shows evidence of genetic heterogeneity with candidate loci on chromosomes 2q36, 10p13, and 5q35
Genomewide search in familial Paget disease of bone shows evidence of genetic heterogeneity with candidate loci on chromosomes 2q36, 10p13, and 5q35
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DOI：
10.1086/323798
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发表时间：
2001-11-01
影响因子：
9.8
通讯作者：
Ralston, SH
中科院分区：
文献类型：
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作者：
Hocking, LJ;Herbert, CA;Ralston, SH
Paget病(PDB)是一种常见的疾病，其特征是局灶性异常，骨转换增加和紊乱。遗传因素在PDB的发病机制中起重要作用，先前的研究表明，PDB样骨发育不良家族性扩张性骨溶解是由编码核因子kappaB受体激活剂(RANK)的TNFRSF11A基因的激活突变引起的；然而，连锁研究和突变筛选排除了绝大多数PDB患者中RANK的参与。为了确定PDB的其他候选基因座，我们对来自62个家族性PDB家系的319个个体进行了全基因组搜索，这些家系主要是英国后裔。作为一个整体，研究组的遗传模式与常染色体显性遗传疾病的传播方式一致。参数多点连锁分析，在异质性模型下，识别出三个染色体区域的LOD得分高于暗示连锁的阈值。它们分别位于2q36(218.24 cM，LOD2.7)、5q35(189.63 cM，LOD3.0)和10p13(41.43 cM，LOD2.6)。对于这些基因座中的每一个，使用Homog进行的正式异质性检验支持具有异质性的连锁模型，而不是没有连锁或具有同质性的连锁。对另一个常染色体显性遗传家系的5q35区域的一系列标记进行的两点连锁分析也支持与候选区域的连锁，D5S2034(187.8 cM)的最大LOD值为3.47.这些数据表明存在几个PDB易感基因座，并在染色体5q35上确定了该病的一个强有力的候选基因座。
Paget disease of bone (PDB) is a common disorder characterized by focal abnormalities of increased and disorganized bone turnover. Genetic factors are important in the pathogenesis of PDB, and previous studies have shown that the PDB-like bone dysplasia familial expansile osteolysis is caused by activating mutations in the TNFRSF11A gene that encodes receptor activator of nuclear factor kappaB (RANK); however, linkage studies, coupled with mutation screening, have excluded involvement of RANK in the vast majority of patients with PDB. To identify other candidate loci for PDB, we conducted a genomewide search in 319 individuals, from 62 kindreds with familial PDB, who were predominantly of British descent. The pattern of inheritance in the study group as a whole was consistent with autosomal dominant transmission of the disease. Parametric multipoint linkage analysis, under a model of heterogeneity, identified three chromosomal regions with LOD scores above the threshold for suggestive linkage. These were on chromosomes 2q36 (LOD score 2.7 at 218.24 cM), 5q35 (LOD score 3.0 at 189.63 cM), and 10p13 (LOD score 2.6 at 41.43 cM). For each of these loci, formal heterogeneity testing with HOMOG supported a model of linkage with heterogeneity, as opposed to no linkage or linkage with homogeneity. Two-point linkage analysis with a series of markers from the 5q35 region in another large kindred with autosomal dominant familial PDB also supported linkage to the candidate region with a maximum LOD score of 3.47 at D5S2034 (187.8 cM). These data indicate the presence of several susceptibility loci for PDB and identify a strong candidate locus for the disease, on chromosome 5q35.