title: Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget's disease.
abstract: Most patients with juvenile Paget's disease (JPD) are homozygous for mutations in the gene TNFRSF11B that result in deficiency of osteoprotegerin (OPG) - a key regulator of bone turnover. So far, about 10 different OPG mutations have been described. The current study presents two novel OPG mutations in JPD patients. Patient 1 was diagnosed at the age of 9months when he presented with inability to sit up, slow growth, marked bone pain and very high levels of serum alkaline phosphatase. Patient 2 presented a milder phenotype. He was initially diagnosed with osteogenesis imperfecta, and although he had numerous fractures and bone deformity, he was still independently mobile at the age of 19years, when a diagnosis of JPD was confirmed. Sequence analysis of DNA samples from the patients determined two novel homozygous mutations in TNFSRF11B. Patient 1 (severe phenotype) had a large (245-251kbp) homozygous deletion beginning in intron 1 that resulted in loss of 4 of the 5 exons of TNFSRF11B, including the whole ligand-binding domain. Patient 2 had a homozygous missense mutation resulting in a Thr>Pro change in exon 2 of TNFSRF11B that is predicted to disrupt the OPG ligand-binding domain. Taken in conjunction with other published cases, these results are consistent with the hypothesis that the most severe phenotypes in JPD are seen in patients with major gene deletions or mutations affecting cysteine residues in the ligand-binding domain.
authors.affiliation: Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Electronic address: d.naot@auckland.ac.nz.
authors.forename: Dorit
authors.initials: D
authors.lastname: Naot
authors.affiliation: Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Electronic address: a.choi@auckland.ac.nz.
authors.forename: Ally
authors.initials: A
authors.lastname: Choi
authors.affiliation: Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Electronic address: d.musson@auckland.ac.nz.
authors.forename: David Shaun
authors.initials: DS
authors.lastname: Musson
authors.affiliation: Pediatric Genetics Unit, Hacettepe University, Ihsan Doğramaci Children's Hospital, Ankara, Turkey. Electronic address: pelinozlem@hacettepe.edu.tr.
authors.forename: Pelin Özlem
authors.initials: PÖ
authors.lastname: Simsek Kiper
authors.affiliation: Pediatric Genetics Unit, Hacettepe University, Ihsan Doğramaci Children's Hospital, Ankara, Turkey. Electronic address: geutine@hacettepe.edu.tr.
authors.forename: Gulen Eda
authors.initials: GE
authors.lastname: Utine
authors.affiliation: Pediatric Genetics Unit, Hacettepe University, Ihsan Doğramaci Children's Hospital, Ankara, Turkey. Electronic address: kbodur@hacettepe.edu.tr.
authors.forename: Koray
authors.initials: K
authors.lastname: Boduroglu
authors.affiliation: Department of Medicine, IN University School of Medicine, IN, USA. Electronic address: mpeacock@iu.edu.
authors.forename: Munro
authors.initials: M
authors.lastname: Peacock
authors.affiliation: Department of Pediatrics, Riley Hospital for Children, IN University School of Medicine, IN, USA. Electronic address: dimeglio@iu.edu.
authors.forename: Linda A
authors.initials: LA
authors.lastname: DiMeglio
authors.affiliation: Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. Electronic address: t.cundy@auckland.ac.nz.
authors.forename: Tim
authors.initials: T
authors.lastname: Cundy
mesh_terms: D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010001:Osteitis Deformans / Q000000981:diagnostic imaging / Q000235:genetics*; D053244:Osteoprotegerin / Q000235:genetics*; D011247:Pregnancy; D011859:Radiography; D055815:Young Adult
chemical_list: D053244:Osteoprotegerin
keywords: Genotype–phenotype; Rare bone diseases; Skeletal deformity