Genomewide Search in Familial Paget Disease of Bone Shows Evidence of Genetic Heterogeneity with Candidate Loci on Chromosomes 2q36, 10p13, and 5q35

Paget disease of bone (PDB) is a common disorder characterized by focal abnormalities of increased and disorganized bone turnover. Genetic factors are important in the pathogenesis of PDB, and previous studies have shown that the PDB-like bone dysplasia familial expansile osteolysis is caused by act...

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Published in:	American journal of human genetics Vol. 69; no. 5; pp. 1055 - 1061
Main Authors:	Hocking, Lynne J., Herbert, Craig A., Nicholls, Rosie K., Williams, Fiona, Bennett, Simon T., Cundy, Tim, Nicholson, Geoff C., Wuyts, Wim, Van Hul, Wim, Ralston, Stuart H.
Format:	Journal Article
Language:	English
Published:	Chicago, IL Elsevier Inc 01-11-2001 University of Chicago Press The American Society of Human Genetics
Subjects:	Biological and medical sciences Chromosome Mapping Chromosomes, Human, Pair 10 - genetics Chromosomes, Human, Pair 2 - genetics Chromosomes, Human, Pair 5 - genetics Diseases of the osteoarticular system Female Genetic Heterogeneity Genome, Human Glycoproteins - genetics Humans Lod Score Male Malformations and congenital and or hereditary diseases involving bones. Joint deformations Medical sciences Osteitis Deformans - genetics Osteoprotegerin Pedigree Receptors, Cytoplasmic and Nuclear - genetics Receptors, Tumor Necrosis Factor Human Paget disease of bone Linkage Family study Pathogenesis Diseases of the osteoarticular system Chromosome A2 Bone disease Chromosome B5 Chromosome C10 Genetic determinism Heterogeneity Gene Locus
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Summary:	Paget disease of bone (PDB) is a common disorder characterized by focal abnormalities of increased and disorganized bone turnover. Genetic factors are important in the pathogenesis of PDB, and previous studies have shown that the PDB-like bone dysplasia familial expansile osteolysis is caused by activating mutations in the TNFRSF11A gene that encodes receptor activator of nuclear factor κB (RANK); however, linkage studies, coupled with mutation screening, have excluded involvement of RANK in the vast majority of patients with PDB. To identify other candidate loci for PDB, we conducted a genomewide search in 319 individuals, from 62 kindreds with familial PDB, who were predominantly of British descent. The pattern of inheritance in the study group as a whole was consistent with autosomal dominant transmission of the disease. Parametric multipoint linkage analysis, under a model of heterogeneity, identified three chromosomal regions with LOD scores above the threshold for suggestive linkage. These were on chromosomes 2q36 (LOD score 2.7 at 218.24 cM), 5q35 (LOD score 3.0 at 189.63 cM), and 10p13 (LOD score 2.6 at 41.43 cM). For each of these loci, formal heterogeneity testing with HOMOG supported a model of linkage with heterogeneity, as opposed to no linkage or linkage with homogeneity. Two-point linkage analysis with a series of markers from the 5q35 region in another large kindred with autosomal dominant familial PDB also supported linkage to the candidate region with a maximum LOD score of 3.47 at D5S2034 (187.8 cM). These data indicate the presence of several susceptibility loci for PDB and identify a strong candidate locus for the disease, on chromosome 5q35.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0002-9297 1537-6605
DOI:	10.1086/323798