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TNFSF11
TNF superfamily member 11
TNFSF11 is located on the long (q) arm of chromosome 13, at band 13q14.11. Arm ratio per GRCh38 - banding schematic.
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Overview
TNFSF11 belongs to the tumour necrosis factor superfamily and encodes a protein commonly known as RANKL (receptor activator of nuclear factor kappa-B ligand). This signalling molecule plays a central role in skeletal physiology by regulating the development and function of osteoclasts, the specialised cells responsible for breaking down bone tissue during normal remodelling. Beyond bone metabolism, RANKL contributes to immune cell maturation and lymph node formation. Disruption of TNFSF11 function can impair the balance between bone formation and resorption, resulting in skeletal conditions characterised by abnormally dense bones and delayed tooth eruption.
What the gene does
The TNFSF11 protein exists in both membrane-bound and soluble forms, both of which bind to the RANK receptor on precursor cells, triggering signalling cascades that promote osteoclast differentiation and activation. Osteoclasts are multinucleated cells that dissolve mineralised bone matrix, a process essential for bone growth, repair, and calcium homeostasis. RANKL activity is tightly regulated by osteoprotegerin, a decoy receptor that prevents excessive bone resorption. In the immune system, RANKL supports the development of dendritic cells and the formation of lymphoid tissue structures. The protein coordinates these diverse functions through activation of nuclear factor kappa-B and related downstream pathways that control cell survival, differentiation, and inflammatory responses.
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Chromosome location
TNFSF11 is located on the long arm of chromosome 13 at band 13q14.11. This chromosomal region contains several genes involved in immune regulation and skeletal development. The gene encodes a protein of 317 amino acids, with alternative splicing producing transcript variants that differ in their cellular localisation and signalling properties.
Protein structure
The TNFSF11 protein contains a disordered region spanning amino acids 1 to 43 at the N-terminus, followed by a tumour necrosis factor homology domain (THD) extending from amino acids 164 to 313. The THD is characteristic of TNF superfamily members and mediates receptor binding and trimer formation, which is necessary for RANK activation. The N-terminal disordered region may contribute to protein flexibility and interaction with regulatory factors, though its precise functional role remains under investigation.
Key variants
Pathogenic variants in TNFSF11 are inherited in an autosomal recessive pattern, meaning that two altered copies of the gene must be present for skeletal abnormalities to manifest. Loss-of-function changes that reduce or eliminate RANKL activity impair osteoclast formation, leading to defective bone resorption. The variant spectrum includes missense substitutions affecting the TNF homology domain and nonsense mutations that truncate the protein before critical functional regions.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TNFSF11 cause autosomal recessive osteopetrosis, a condition characterised by increased bone density due to impaired osteoclast function. Affected individuals may present with fractures despite dense bones, delayed tooth eruption, vision or hearing loss from nerve compression, and increased susceptibility to infection. The severity and age of onset can vary depending on the specific variants inherited. TNFSF11-related skeletal dysplasia shares overlapping features with other forms of osteopetrosis but is distinguished by the underlying molecular defect in RANKL signalling.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TNFSF11 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
TNFSF11 is listed on several NHS Genomic Medicine Service PanelApp panels, reflecting its clinical relevance. It appears on the Osteopetrosis panel (green classification, R104.4) and the broader Skeletal dysplasia panel (green classification, R104), indicating strong evidence for its role in these conditions. The gene also features on the COVID-19 research panel (green classification), acknowledging emerging interest in RANKL's immune-related functions during infectious disease.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the TNFSF11 gene do?
TNFSF11 encodes RANKL, a signalling protein that controls the formation and activity of osteoclasts, cells that break down bone tissue. It is essential for normal bone remodelling, tooth eruption, and aspects of immune system development.
How are TNFSF11 variants inherited?
Pathogenic variants in TNFSF11 follow an autosomal recessive inheritance pattern. An individual must inherit two altered copies, one from each parent, to develop skeletal abnormalities. Carriers with one variant typically do not show symptoms.
Can TNFSF11 variants affect teeth as well as bones?
Yes, because RANKL is required for tooth eruption, individuals with biallelic TNFSF11 variants often experience delayed or absent eruption of primary and permanent teeth alongside bone abnormalities.