Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget's disease

Dorit Naot, Ally Choi, David Shaun Musson, Pelin Özlem Simsek Kiper, Gulen Eda Utine, Koray Boduroglu, Munro Peacock, Linda DiMeglio, Tim Cundy

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 9. months 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 19. years, 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 (245-251. kbp) 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.

Original languageEnglish
Pages (from-to)6-10
Number of pages5
JournalBone
Volume68
DOIs
StatePublished - 2014

Fingerprint

Osteoprotegerin
Mutation
Genes
Phenotype
Exons
RANK Ligand
Ligands
Osteogenesis Imperfecta
Hyperostosis corticalis deformans juvenilis
Bone Remodeling
Sequence Deletion
Bone Development
Bone Fractures
Gene Deletion
Missense Mutation
DNA Sequence Analysis
Introns
Cysteine
Alkaline Phosphatase
Pain

Keywords

  • Genotype-phenotype
  • Rare bone diseases
  • Skeletal deformity

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology
  • Medicine(all)

Cite this

Naot, D., Choi, A., Musson, D. S., Simsek Kiper, P. Ö., Utine, G. E., Boduroglu, K., ... Cundy, T. (2014). Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget's disease. Bone, 68, 6-10. https://doi.org/10.1016/j.bone.2014.07.034

Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget's disease. / Naot, Dorit; Choi, Ally; Musson, David Shaun; Simsek Kiper, Pelin Özlem; Utine, Gulen Eda; Boduroglu, Koray; Peacock, Munro; DiMeglio, Linda; Cundy, Tim.

In: Bone, Vol. 68, 2014, p. 6-10.

Research output: Contribution to journalArticle

Naot, Dorit ; Choi, Ally ; Musson, David Shaun ; Simsek Kiper, Pelin Özlem ; Utine, Gulen Eda ; Boduroglu, Koray ; Peacock, Munro ; DiMeglio, Linda ; Cundy, Tim. / Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget's disease. In: Bone. 2014 ; Vol. 68. pp. 6-10.
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