Paget Disease of Bone: Mapping of Two Loci at 5q35-qter and 5q31

Abstract

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.

Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

“…(23,25,26) This hypothesis was confirmed by genetic studies performed so far, with identification of disease-causing mutations in the SQSTM1 gene (34,42,43) and the presence of susceptibility variants in the gene encoding osteoprotegerin (OPG). (71,72) The latter was found by association studies, and as briefly described in the Introduction, the TNFRSF11A gene encoding RANK is for several reasons another strong candidate gene to contain such variants.…”

“…Genetic linkage studies in multicase PDB families have resulted in the identification of 7 PDB loci (PDB1-7). (29)(30)(31)(32)(33)(34)(35) However, several of these loci are currently assumed to be falsepositive results. (36)(37)(38)(39)(40)(41) Until now, only one PDB-causing gene has been identified: the sequestosome1 gene (SQSTM1; MIM 601530), located in the PDB3 region on chromosome 5q35.…”

“…(36)(37)(38)(39)(40)(41) Until now, only one PDB-causing gene has been identified: the sequestosome1 gene (SQSTM1; MIM 601530), located in the PDB3 region on chromosome 5q35. (34,42,43) To date, 23 SQSTM1 mutations have been found in 28.3% of patients with familial PDB and 7.5% of those with sporadic PDB. (37,42,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) Furthermore, in most cases, the same missense mutation was identified (C1215T, P392L).…”

Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone

“…The 10p13 (PDB6) locus was suggested in a genome-wide scan linkage analysis in British PDB families [6,7], but no PDB-causing mutation has been reported in this locus until now. Furthermore, this locus was not suggested either in the genome-wide scan of three French-Canadian families, who were linked to PDB3 in one family and to the PDB4 locus in the two others [4]. However, linkage to PDB6 was not investigated in the remaining PDB families in the French-Canadian population.…”

“…Genetic heterogeneity has been demonstrated in familial forms of PDB, which have been linked to several chromosomal regions. In the 5q35-qter (PDB3) locus [4], the first and still most common mutation, P392L, within the Sequestosome 1 (SQSTM1) gene was reported in FrenchCanadian PDB patients [5]. The 10p13 (PDB6) locus was suggested in a genome-wide scan linkage analysis in British PDB families [6,7], but no PDB-causing mutation has been reported in this locus until now.…”