Idiopathic Hyperphosphatasia and TNFRSF11B Mutations: Relationships Between Phenotype and Genotype

Abstract

Homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin, were found in affected members from six of nine families with idiopathic hyperphosphatasia. The severity of the phenotype was related to the predicted effects of the mutations on osteoprotegerin function.Introduction: Idiopathic hyperphosphatasia (IH) is a rare high bone turnover congenital bone disease in which affected children are normal at birth but develop progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and deafness. There is, however, considerable phenotypic variation from presentation in infancy with severe progressive deformity through to presentation in late childhood with minimal deformity. Two recent reports have linked idiopathic hyperphosphatasia with deletion of, or mutation in, the TNFRSF11B gene that encodes osteoprotegerin (OPG), an important paracrine modulator of RANKL-mediated bone resorption. Materials and Methods:We studied subjects with a clinical diagnosis of IH and unaffected family members from nine unrelated families. Clinical, biochemical, and radiographic data were collected, and genomic DNA examined for mutations in TNFRSF11B. The relationship between the mutations, their predicted effects on OPG function, and the phenotype were then examined. Results: Of the nine families studied, affected subjects from six were homozygous for novel mutations in TNFRSF11B. Their parents were heterozygous, consistent with autosomal recessive inheritance. Four of the six mutations occurred in the cysteine-rich ligand-binding domain and are predicted to disrupt binding of OPG to RANKL. Missense mutations in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype (deformity developing before 18 months age and severe disability), as was a large deletion mutation. Non-cysteine missense mutations in the ligand-binding domain were associated with an intermediate phenotype (deformity recognized around the age of 5 years and an increased rate of long bone fracture). An insertion/deletion mutation at the C-terminal end of the protein was associated with the mildest phenotype. Conclusion: Mutations in TNFRSF11B account for the majority of, but not all, cases of IH, and there are distinct genotype-phenotype relationships.

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

“…This disease presents in infancy or early childhood with pain from debilitating fractures and deformities owing to a markedly accelerated rate of bone remodeling throughout the skeleton. (43) Some missense mutations in the CRD are associated with severe osteoporotic phenotypes, (44,45) probably owing to the lack of ligand binding of OPG. In addition, a frameshift mutation (D198RfsX7) resulting in deletion of the DDHDs and the HBD has been reported in a severe juvenile Paget disease patient.…”

“…In addition, a frameshift mutation (D198RfsX7) resulting in deletion of the DDHDs and the HBD has been reported in a severe juvenile Paget disease patient. (45) There is a possibility that mRNA stability was decreased and protein expression level of OPG also was decreased. (45) However, on the basis of this study, it can be explained that only the CRD form of OPG, which is synthesized according to the mutation, cannot regulate RANKL sorting in the Golgi apparatus, resulting in the marked increase in the amount of RANKL at the osteoblastic cell surface.…”

“…(45) There is a possibility that mRNA stability was decreased and protein expression level of OPG also was decreased. (45) However, on the basis of this study, it can be explained that only the CRD form of OPG, which is synthesized according to the mutation, cannot regulate RANKL sorting in the Golgi apparatus, resulting in the marked increase in the amount of RANKL at the osteoblastic cell surface. Another frameshift mutation (D323FfsX4), resulting in deletion of the HBD, has been reported in a relatively mild juvenile Paget disease patient.…”

Characterisation of Osteoprotegerin Autoantibodies in Coeliac Disease

“…The importance of this pathway in bone metabolism is demonstrated by the fact that pharmacological blockade of RANKL is an effective treatment for osteoporosis (6) and that loss of function mutations of OPG in humans lead to raised bone turnover and multiple fractures in childhood (7).…”

Periostin and sclerostin levels in juvenile Paget�s disease

“…Patients present early skeletal implication, including malformations and low-energy fractures, and later non-skeletal manifestations, including retinopathy, hearing loss, vascular calcification and internal carotid artery aneurysms formation (1)(2)(3). Most patients have homozygous loss-of-function mutations of the TNFRSF11B gene, resulting in deficient or non-functioning osteoprotegerin (2,4). To the best of our knowledge, JPD due to homozygosity for the TNFRSF11B "Balkan mutation" (966_969delTGACinsCTT), resulting in non-functioning osteoprotegerin, has been described in only five patients todate (5).…”