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 straight theta= .1. 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 straight 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.

To evaluate the 67Ga lung uptake as an indicator of inflammatory activity in asbestosis, we obtained 67Ga lung scans in 58 long-term asbestos workers. The 67Ga localized excessively in the lungs of 17 of the 21 workers with asbestosis. Among workers without sufficient criteria for the diagnosis of asbestosis, the 67Ga scan index was significantly increased in 43% (16 of 37). Among the 16 with positive 67Ga scan, abnormal pressure-volume curve and/or gas exchange data were found in 87%, whereas in the 21 workers with negative 67Ga scan, similar abnormalities were found in only 29%. In the sheep model of the disease, bronchoalveolar analysis after 67Ga scan demonstrated that the excessive uptake of 67Ga in asbestosis is caused by enhanced serum protein leakage and macrophage accumulation in the lung. Thus, 67Ga scanning in asbestos workers may be a useful indicator of early lung damage.