Alt. symbols: PDB2 | LOH18CR1 | RANK | CD265 | FEO

Approved name: TNF receptor superfamily member 11a
Alt. names: tumor necrosis factor receptor superfamily, member 11a, activator of NFKB, Paget disease of bone 2, loss of heterozygosity, 18, chromosomal region 1, tumor necrosis factor receptor superfamily, member 11a, NFKB activator

Location: 18q21.33: 62325287 - 62391288 (+)
Gene type: protein_coding, 4 transcripts.

Scores: LoFtool: 0.261000 | pLI: 0.87991735 | LOEUF: 0.597

HGNC: 11908

NCBI: 8792, RefSeq: NG_008098.1

Ensembl: ENSG00000141655.18

LRG_194 | Status: public

OMIM: 603499

Expression | ProteinAtlas

TNFRSF11A encodes the transmembrane protein RANK, which stands for receptor activator of NF-kappa-B. After binding its ligand RANKL, RANK activates signaling pathways such as NF-kB, JNK, ERK, p38, and Akt/PKB, through TRAF protein phosphorylation. RANK is a member of the TNF-receptor superfamily that is important for bone metabolism and immune function and also plays a regulatory role in organogenesis and cancers. In association with its ligand - RANKL -, RANK promotes the survival of dendritic cells (DCs), controls self-tolerance and oral-tolerance through regulatory T cell functions, and it is critical for the development and organization of several lymphoid organs. The RANKL-RANK interaction controls the differentiation of microfold cells, specialized epithelial cells in mucosal tissues, that take up and transpose antigen particles to control the immune response against pathogens or commensal bacterium. RANK controls the development of epithelial cells localized in the thymic medulla (mTECs), and therefore, it is critical for the elimination of self-antigen reactive T cells in the thymus and for the suppression of autoimmunity (Akiyama, Shinzawa and Akiyama, 2012; Guerrini and Takayanagi, 2014). RANK also has a potential role in B cell immunopathology, as malignant B cells in Hodkin’s lymphoma have been shown to co-express RANK and RANKL and chronic lymphocytic leukemia (CLL) B cells have been reported to show increased RANK/RANKL levels in comparison with normal B cells (Secchiero et al., 2006).

RANK is involved in an essential signalling pathway for the generation of osteoclasts, a type of cell involved in bone remodeling by resorption of bone tissue. With regard to this biological function, monoallelic mutations in TNFRSF11A (the gene encoding RANK) may cause autosomal dominant familial expansile osteolysis (FEO) [MIM:174810], or early-onset Paget disease of bone 2 [MIM:602080]. Biallelic mutations in the gene cause autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobu linemia (Osteopetrosis, autosomal recessive 7) [MIM:612301]. Heterozygous insertion mutations in TNFRSF11A (c.75dup27, c.83dup18, c.84dup18 and c.87dup15) have been associated with FEO and/or Paget disease of bone in several unrelated familial cases (Hughes et al., 2000; Palenzuela et al., 2002; Elahi et al., 2007; Whyte et al., 2014). Expression analysis for mutations c.75dup27 and c.84dup18 showed a lack of normal cleavage of the signal peptide, altered RANK protein levels and a gain-of-function of the protein in general. The autosomal recessive disease, osteopetrosis, is caused by homozygous or compound heterozygous missense mutations in TNFRSF11A. In detail, homozygosity for variant p.Gly53Arg has been detected in two unrelated patients with osteopetrosis and another variant, p.Arg170Gly, has been detected in homozygosity in two related patients with osteopetrosis and hypogammaglobulinemia linked to reduced B cell levels (Guerrini et al., 2008). Compound heterozygous mutations in the gene were detected in two unrelated patients with osteopetrosis, both carrying the variant p.Cys175Arg and variants p.Arg129Cys or p.Ala244Ser in addition. Furthermore, there are several somatic missense mutations in TNFRSF11A (p.Gly117Glu, p.Ser121Ile, p.Phe159Leu, p.Lys240Glu and p.Pro591Leu) detected in human diffuse large B cell lymphoma specimens indicating that alterations in the gene may also contribute to B cell-related malignancy (Compagno et al., 2009). [Load More]