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

Abstract

Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during 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 D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.

Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation

“…Five families affl icted with FEO and one sporadic case of FEO have been described [4][5][6]. The largest of these pedigrees was from Northern Ireland, and the others were from Germany, the United States, and Spain.…”

“…The largest of these pedigrees was from Northern Ireland, and the others were from Germany, the United States, and Spain. The disease was originally linked to chromosome 18 in the Irish family and, later, TNFRSF11A was identifi ed as the causative gene in all the familial and sporadic cases [4][5][6][7]. TNFRSF11A encodes receptor activator of nuclear factor-κB (RANK) and was considered an appropriate candidate gene because RANK is expressed on osteoclast precursor cells and is a receptor for RANK ligand-mediated signaling affecting osteoclast formation, differentiation, and function [8].…”

“…TNFRSF11A encodes receptor activator of nuclear factor-κB (RANK) and was considered an appropriate candidate gene because RANK is expressed on osteoclast precursor cells and is a receptor for RANK ligand-mediated signaling affecting osteoclast formation, differentiation, and function [8]. An identical in-frame 18-base pair (18-bp) tandem duplication (84dup18; g.84_101dupCTGCTCTGCGCGCTGCTC; c.46_63dupCTGCTCTGCGCGCTGCTC) in the fi rst exon of TNFRSF11A, affecting the signal peptide region of RANK, was identifi ed as the disease-causing mutation in four of the families [4,5]. The mutation existed in the heterozygous state in affected individuals.…”

“…Expression level and cleavage of the signal peptide of recombinant RANK carrying the mutation were shown to be perturbed. Functionally, the mutation caused increased RANK-mediated nuclear factor-κB signaling in vitro [4]. The mutation in the remaining familial and sporadic cases was another 18-bp tandem duplication (83dup18; g.83_100dupGCTGCTCT GCGCGCTGCT;…”

Identification of genetic modifiers of monogenic (bone) diseases: New tools available, but with limitations

“…Closely related but clearly distinguishable phenotypes were associated with duplications of different size in that part of the gene encoding RANK. (5) Also for the TGF-b1 gene, such a different size of duplication might cause minor clinical differences. Although the underlying mechanisms are not completely understood, for neither the RANK protein (reviewed and discussed in Crockett et al (6) ) nor the TGF-b1 protein, (7) in both cases they seem to result in overactivation of the pathway.…”