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

Paget disease of bone is characterized by focal increases of the bone-remod eling process. It is the second most common metabolic bone disease after os teoporosis. Genetic factors play a major role in the etiology of Paget dise ase 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 charact erized. To decipher the molecular basis of Paget disease of bone, we perfor med genetic linkage analysis in 24 large French Canadian families (479 indi viduals) in which the disorder was segregating as an autosomal dominant tra it. After exclusion of PDB2, a genomewide scan was performed on the three m ost informative family nuclei. LOD scores >1.0 were observed at seven locat ions. 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 w as obtained at D5S2073, at theta = .01. The same characteristic haplotype w as 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 o f 3.70 was detected at D5S500 with theta = .00. Recombination events refine d the 5q31 region within 12.2 cM, between D5S642 and D5S1972. These observa tions demonstrate the mapping of two novel loci for Paget disease of bone a nd provide further evidence for genetic heterogeneity of this highly preval ent disorder. It is proposed that the 5q35-qter and 5q31 loci be named "PDB 3" and "PDB4," respectively.