A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype.
Idiopathic hyperphosphatasia is an autosomal recessive bone disease characterized by deformities of long bones, kyphosis and acetabular protrusion, increasing in severity as affected children pass through adolescence. Biochemical and histological evidence indicate that there is extremely rapid bone turnover, with indices of both bone resorption and formation greatly increased. A genome-wide search, in a family with three children affected by idiopathic hyperphosphatasia, suggested linkage to a locus on the long arm of chromosome 8 (8q24). The gene TNFRSF11B encoding osteoprotegerin (OPG), which lies within this locus, was an obvious candidate, given the critical role of OPG in regulating osteoclast development. All three affected siblings were homozygous for a 3 bp inframe deletion in exon 3 of the TNFRSF11B gene, resulting in the loss of an aspartate residue. Their parents (who were first cousins) were heterozygous for the mutation. Recombinant wild-type and mutant OPG cDNAs were expressed in human epithelial kidney cells, and secreted OPG was collected from the conditioned medium. In vitro measurements of bone resorption showed that wild-type OPG suppressed bone resorption, whereas the mutant form did not, confirming this to be an inactivating mutation. This description of abnormal OPG function in humans expands the spectrum of genetic bone diseases arising from perturbations of the OPG/RANK-L/RANK system that regulates osteoclastogenesis.
Department of Medicine, Faculty of Medicine and Health Science, University of Auckland, New Zealand. t.cundy@auckland.ac.nz
Tim
T
Cundy
Madhuri
M
Hegde
Dorit
D
Naot
Belinda
B
Chong
Alan
A
King
Robyn
R
Wallace
John
J
Mulley
Donald R
DR
Love
Joerg
J
Seidel
Matthew
M
Fawkner
Tatjana
T
Banovic
Karen E
KE
Callon
Andrew B
AB
Grey
Ian R
IR
Reid
Catherine A
CA
Middleton-Hardie
Jillian
J
Cornish
D000293:Adolescent; D000328:Adult; D001842:Bone and Bones / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005808:Genes, Recessive; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics*; D053244:Osteoprotegerin; D010375:Pedigree; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor
D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human