PAGETS-DISEASE OF BONE - EVIDENCE FOR A SUSCEPTIBILITY LOCUS ON CHROMOSOME 18Q AND FOR GENETIC-HETEROGENEITY

Paget's disease of bone is a common condition characterized by bone pa in, deformity, pathological fracture, and an increased incidence of os teosarcoma, Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis of the disease remains unclear. Previ ous genetic linkage studies have mapped the rare Paget's disease-like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21 -22, and recent work has shown evidence of linkage between this locus and Paget's disease in one family, Here we studied the relationship be tween the 18q21-22 locus and Paget's disease in eight large multiplex families from diverse ethnic backgrounds with inherited Pagers disease . Pagers disease,vas inherited as an autosomal dominant trait in all f amilies, with high penetrance by the sixth decade, Analysis of seven h ighly polymorphic markers from chromosome 18q21-22 showed positive sum mated two-point log(10) odds ratio (lodscores) of +2.97 with the marke r D18S42 at a recombination fraction (theta) = 0.05, and of +2.95 with the marker D18S60 at theta = 0.00, values which are close to the cut- off of +3.0, which is generally accepted as evidence of linkage. Segre gation analysis of the haplotypes and formal statistical analysis usin g the HOMOG program provided evidence for genetic heterogeneity, howev er, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025), Mul tipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum sum mated lodscore of 3.89 at the marker D18S465. In the three nonlinked f amilies, negative multipoint results were obtained for the whole regio n, with lodscores below -2.0 in one family, excluding this as a candid ate locus for the disease. Our studies demonstrate the importance of h ereditary factors in the pathogenesis of Paget's disease and confirm e vidence of linkage between Paget's disease and chromosome 18q21-22 in some families. This raises the possibility that Paget's disease and FE O may share a common molecular basis, perhaps due to different mutatio ns in the same gene or family of genes. Data from three families did n ot support evidence of linkage to 18q21-22 however, indicating that Pa get's disease is genetically heterogeneous and suggests the presence o f at least one additional locus which remains to be discovered.