Mutation Screening of the TNFRSF11A Gene Encoding Receptor Activator of NFkB (RANK) in Familial and Sporadic Paget's Disease of Bone and Osteosarcoma

Abstract

Paget's disease of bone (PDB) is a common disorder characterized by focal areas of increased and disorganized osteoclastic bone resorption, leading to bone pain, deformity, pathological fracture, and an increased risk of osteosarcoma. Genetic factors play an important role in the pathogenesis of Paget's disease. In some families, the disease has been found to be linked to a susceptibility locus on chromosome 18q21-22, which also contains the gene responsible for familial expansile osteolysis (FEO)--a rare bone dysplasia with many similarities to Paget's disease. Insertion mutations of the TNFRSF11A gene encoding Receptor Activator of NF kappa B (RANK) have recently been found to be responsible for FEO and rare cases of early onset familial Paget's disease. Loss of heterozygosity (LOH) affecting the PDB/FEO critical region has also been described in osteosarcomas suggesting that TNFRSF11A might also be involved in the development of osteosarcoma. In order to investigate the possible role of TNFRSF11A in the pathogenesis of Paget's disease and osteosarcoma, we conducted mutation screening of the TNFRSF11A gene in patients with familial and sporadic Paget's disease as well as DNA extracted from Pagetic bone lesions, an osteosarcoma arising in Pagetic bone and six osteosarcoma cell lines. No specific abnormalities of the TNFRSF11A gene were identified in a Pagetic osteosarcoma, the osteosarcoma cell lines, DNA extracted from Pagetic bone lesions, or DNA extracted from peripheral blood in patients with familial or sporadic Paget's disease including several individuals with early onset Paget's disease. These data indicate that TNFRSF11A mutations contribute neither to the vast majority of cases of sporadic or familial PDB, nor to the development of osteosarcoma.

Early onset Paget's disease of bone caused by a novel mutation (78dup27) of the TNFRSF11A gene in a Chinese family

“…The latter is commonly caused by SQSTM1 mutations [5][6][7] . No functional mutations in TNFRSF11A were found in six Caucasian patients with early onset PDB (age of onset below 40 years) or in 64 individuals affected with familial PDB of Caucasian origin [16] . So far, no SQSTM1 mutations have been detected in Asian PDB patients.…”

Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

“…(38,71,72) Therefore, it seems very possible that polymorphisms in the TNFRSF11A gene contribute to the susceptibility for the sporadic form of PDB despite the fact that mutations have not been found in typical PDB patients. (38)(39)(40) This study was initiated in the Belgian study population with a power of 75% to find an association with an OR of 1.5 for an SNP with an MAF of 25%. Furthermore, the availability of two populations for replication studies increased the power and together delivered a chance of 94% to find an OR of 1.5 for an SNP with an MAF of 25%.…”

“…(29)(30)(31)(32)(33)(34)(35) However, several of these loci are currently assumed to be falsepositive results. (36)(37)(38)(39)(40)(41) Until now, only one PDB-causing gene has been identified: the sequestosome1 gene (SQSTM1; MIM 601530), located in the PDB3 region on chromosome 5q35. (34,42,43) To date, 23 SQSTM1 mutations have been found in 28.3% of patients with familial PDB and 7.5% of those with sporadic PDB.…”

“…(70) However, no TNFRSF11A mutations were reported in PDB patients. (38)(39)(40) We and others reported association between sporadic PDB and polymorphisms in the TNFRSF11B gene encoding osteoprotegerin (OPG; MIM 602643), a decoy receptor for RANKL, indicating that variation in the OPG/RANKL/RANK-NFkB pathway influences the risk to develop PDB. (38,71,72) In this study we evaluated whether polymorphisms in the TNFRSF11A gene encoding RANK contribute to the development of PDB in three different European populations of sporadic PDB patients.…”

Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3-18q22

“…7 ± 9 Loss of heterocygosity (LOH) analysis in sporadic and Paget associated osteosarcomas revealed a region of minimum LOH between markers D18S60 and D18S42, suggesting the presence of a PDB and osteosarcoma related tumour suppressor gene in this region. 9 The identity of the tumor related gene is not clear, but it is probably not identical with RANK, since no mutations in RANK were detected in Paget related osteosarcomas 7 and since the activating nature of the identified FEO-and PDBmutations in RANK is not compatible with the loss of function type of mutation (suggested by LOH) in the assumed PDB osteosarcoma gene. To evaluate the role of the 18q region in CRMO we conducted a family based association study with markers D18S1148 and D18S60 and a mutation screening in patients with CRMO in RANK and two further genes, chosen because of their location in immediate vicinity to D18S60, Phosphatidylinositol glycan, class N (PIGN, Genbank accession NM_012327) and KIAA1468 (Genbank accession AB040901).…”