title: 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.
authors.affiliation: Department of Medical Genetics, The Queen's University of Belfast, Belfast, UK. A.Hughes@qub.ac.uk
authors.forename: A E
authors.initials: AE
authors.lastname: Hughes
authors.forename: S H
authors.initials: SH
authors.lastname: Ralston
authors.forename: J
authors.initials: J
authors.lastname: Marken
authors.forename: C
authors.initials: C
authors.lastname: Bell
authors.forename: H
authors.initials: H
authors.lastname: MacPherson
authors.forename: R G
authors.initials: RG
authors.lastname: Wallace
authors.forename: W
authors.initials: W
authors.lastname: van Hul
authors.forename: M P
authors.initials: MP
authors.lastname: Whyte
authors.forename: K
authors.initials: K
authors.lastname: Nakatsuka
authors.forename: L
authors.initials: L
authors.lastname: Hovy
authors.forename: D M
authors.initials: DM
authors.lastname: Anderson
mesh_terms: D001483:Base Sequence; D002352:Carrier Proteins; D004247:DNA; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D009154:Mutation; D010014:Osteolysis / Q000235:genetics*; D010375:Pedigree; D021382:Protein Sorting Signals / Q000235:genetics*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D021382:Protein Sorting Signals; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D004247:DNA