Paget disease of bone:: Mapping of two loci at 5q35-qter and 5q31

被引:101
作者
Laurin, N
Brown, JP
Lemainque, A
Duchesne, A
Huot, D
Lacourcière, Y
Drapeau, G
Verreault, J
Raymond, V
Morissette, J
机构
[1] CHU Laval, Res Ctr, Mol Endocrinol & Oncol Res Ctr, Quebec City, PQ G1V 4G2, Canada
[2] CHU Laval, Res Ctr, Grp Rech Malad Osseuses Rhumatol Immunol, Quebec City, PQ G1V 4G2, Canada
[3] CHU Laval, Res Ctr, Dept Nucl Med, Quebec City, PQ G1V 4G2, Canada
[4] Ctr Natl Genotypage, Evry, France
[5] Ctr Hosp Reg Amiante, Dept Nucl Med, Thetford Mines, PQ, Canada
[6] Hotel Dieu Arthabaska, Dept Nucl Med, Victoriaville, PQ, Canada
[7] Ctr Univ Sante Estrie, Dept Nucl Med, Sherbrooke, PQ, Canada
基金
加拿大健康研究院;
关键词
D O I
10.1086/322975
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Paget disease of bone is characterized by focal increases of the bone-remodeling process. It is the second most common metabolic bone disease after osteoporosis. Genetic factors play a major role in the etiology of Paget disease of bone, and two loci have been mapped for the disorder: PDB1 and PDB2. The gene(s) causing the typical form of the disorder remains to be characterized. To decipher the molecular basis of Paget disease of bone, we performed genetic linkage analysis in 24 large French Canadian families (479 individuals) in which the disorder was segregating as an autosomal dominant trait. After exclusion of PDB2, a genomewide scan was performed on the three most informative family nuclei. LOD scores >1.0 were observed at seven locations. The 24 families were then used to detect strong evidence for linkage to chromosome 5q35-qter. Under heterogeneity, a maximum LOD score of 8.58 was obtained at D5S2073, at theta = .01. The same characteristic haplotype was carried by all patients in eight families, suggesting a founder effect. A recombination event in a key family confined the disease region within a 6-cM interval between D5S469 and the telomere. The 16 other families, with very low conditional probability of linkage to 5q35-qter, were further used, to map a second locus at 5q31. Under heterogeneity, a maximum LOD score of 3.70 was detected at D5S500 with theta = .00. Recombination events refined the 5q31 region within 12.2 cM, between D5S642 and D5S1972. These observations demonstrate the mapping of two novel loci for Paget disease of bone and provide further evidence for genetic heterogeneity of this highly prevalent disorder. It is proposed that the 5q35-qter and 5q31 loci be named "PDB3" and "PDB4," respectively.
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页码:528 / 543
页数:16
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