Osteoprotegerin deficiency and juvenile Paget's disease.
BACKGROUND
Juvenile Paget's disease, an autosomal recessive osteopathy, is characterized by rapidly remodeling woven bone, osteopenia, fractures, and progressive skeletal deformity. The molecular basis is not known. Osteoprotegerin deficiency could explain juvenile Paget's disease because osteoprotegerin suppresses bone turnover by functioning as a decoy receptor for osteoclast differentiation factor (also called RANK ligand).


METHODS
We evaluated two apparently unrelated Navajo patients with juvenile Paget's disease for defects in the gene encoding osteoprotegerin (TNFRSF11B) using polymerase-chain-reaction (PCR) amplification followed by direct sequencing and Southern blotting of genomic DNA. Genetic markers near TNFRSF11B were evaluated by both a PCR method that involved sequence-tagged site-content mapping of a deletion of TNFRSF11B and PCR spanning the DNA break points.


RESULTS
Both patients had a homozygous deletion of TNFRSF11B, with identical break points, on chromosome 8q24.2. The defect spans approximately 100 kb, but neighboring genes are intact. We found that serum levels of osteoprotegerin and soluble osteoclast differentiation factor were undetectable and markedly increased, respectively.


CONCLUSIONS
Juvenile Paget's disease can result from osteoprotegerin deficiency caused by homozygous deletion of TNFRSF11B.
Whyte
Michael P
MP
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, MO 63131, USA. mwhyte@shrinenet.org
Obrecht
Sara E
SE
Finnegan
Patrick M
PM
Jones
Jonathan L
JL
Podgornik
Michelle N
MN
McAlister
William H
WH
Mumm
Steven
S
D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000097:blood / Q000502:physiology; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D017353:Gene Deletion; D005819:Genetic Markers; D006023:Glycoproteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood / Q000502:physiology; D008969:Molecular Sequence Data; D010001:Osteitis Deformans / Q000235:genetics*; D053244:Osteoprotegerin; D016133:Polymerase Chain Reaction; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction
D002352:Carrier Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human