Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis

Familial expansile osteolysis(1,2) (FEO, MIM 174810) is a rare, autosomal d ominant bone disorder characterized by focal areas of increased bone remode lling. The osteolytic lesions, which develop usually in the long bones duri ng early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18564 and D18551 on chromosome 18q21.2-21.3 in a large Northern Irish family(3,4). The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RAN K is essential in osteoclast formation(6,7). We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four fam ilies with FEO or familial Paget disease of bone (PDB). One was a duplicati on of 18 bases and the other a duplication of 27 bases, both of which affec ted the signal peptide region of the RANK molecule. Expression of recombina nt forms of the mutant RANK proteins revealed perturbations in expression l evels and lack of normal cleavage of the signal peptide. Both mutations cau sed an increase in RANK-mediated nuclear factor-kappa B (NF-kappa B) signal ling in vitro, consistent with the presence of an activating mutation.