Linkage of Paget disease of bone to a novel region on human chromosome 18q23

Good, David A., Busfield, Frances, Fletcher, Barbara H., Duffy, David L., Kesting, Janine B., Andersen, John and Shaw, Joanne T. E. (2002) Linkage of Paget disease of bone to a novel region on human chromosome 18q23. American Journal of Human Genetics, 70 2: 517-525. doi:10.1086/338658

Author Good, David A.
Busfield, Frances
Fletcher, Barbara H.
Duffy, David L.
Kesting, Janine B.
Andersen, John
Shaw, Joanne T. E.
Title Linkage of Paget disease of bone to a novel region on human chromosome 18q23
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2002
Sub-type Article (original research)
DOI 10.1086/338658
Volume 70
Issue 2
Start page 517
End page 525
Total pages 9
Place of publication Chicago
Publisher University of Chicago Press
Collection year 2002
Language eng
Subject C1
321020 Pathology
730114 Skeletal system and disorders (incl. arthritis)
0604 Genetics
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
Abstract Paget disease of bone (PDB) is characterized by increased osteoclast activity and localized abnormal bone remodeling. PDB has a significant genetic component, with evidence of linkage to chromosomes 6p21.3 (PDB1) and 18q21-22 (PDB2) in some pedigrees. There is evidence of genetic heterogeneity, with other pedigrees showing negative linkage to these regions. TNFRSF11A, a gene that is essential for osteoclast formation and that encodes receptor activator of nuclear factor-kappa B (RANK), has been mapped to the PDB2 region. TNFRSF11A mutations that segregate in pedigrees with either familial expansile osteolysis or familial PDB have been identified; however, linkage studies and mutation screening have excluded the involvement of RANK in the majority of patients with PDB. We have excluded linkage, both to PDB1 and to PDB2, in a large multigenerational pedigree with multiple family members affected by PDB. We have conducted a genomewide scan of this pedigree, followed by fine mapping and multipoint analysis in regions of interest. The peak two-point LOD scores from the genomewide scan were 2.75, at D7S507, and 1.76, at D18S70. Multipoint and haplotype analysis of markers flanking D7S507 did not support linkage to this region. Haplotype analysis of markers flanking D18S70 demonstrated a haplotype segregating with PDB in a large subpedigree. This subpedigree had a significantly lower age at diagnosis than the rest of the pedigree (51.2 +/- 8.5 vs. 64.2 +/- 9.7 years; P = .0012). Linkage analysis of this subpedigree demonstrated a peak two-point LOD score of 4.23, at marker D18S1390 (theta = 0), and a peak multipoint LOD score of 4.71, at marker D18S70. Our data are consistent with genetic heterogeneity within the pedigree and indicate that 18q23 harbors a novel susceptibility gene for PDB.
Keyword Genetics & Heredity
Familial Expansile Osteolysis
Transcriptional Repression
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 57 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 63 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 14 Aug 2007, 17:15:01 EST