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Genetics Home Reference: your guide to understanding genetic conditions
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TNFRSF11A

Reviewed February 2010

What is the official name of the TNFRSF11A gene?

The official name of this gene is “tumor necrosis factor receptor superfamily, member 11a, NFKB activator.”

TNFRSF11A is the gene's official symbol. The TNFRSF11A gene is also known by other names, listed below.

What is the normal function of the TNFRSF11A gene?

The TNFRSF11A gene provides instructions for making a protein called receptor activator of NF-κB (RANK). This protein plays an important role in bone remodeling, a normal process in which old bone is broken down and new bone is created to replace it. During bone remodeling, RANK helps direct the formation and function of specialized cells called osteoclasts, which break down bone tissue. RANK is located on the surface of immature osteoclasts, where it receives signals that trigger these cells to mature and become fully functional.

Does the TNFRSF11A gene share characteristics with other genes?

The TNFRSF11A gene belongs to a family of genes called CD (CD molecules). It also belongs to a family of genes called TNFRSF (tumor necrosis factor receptor superfamily).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.

How are changes in the TNFRSF11A gene related to health conditions?

Paget disease of bone - caused by mutations in the TNFRSF11A gene

At least two very similar mutations in the TNFRSF11A gene have been found to cause the rare, early-onset form of Paget disease of bone. Both mutations are duplications, which means that they abnormally copy a segment of genetic material within the gene. Each of these mutations results in the production of a RANK protein that contains several extra protein building blocks (amino acids).

Through a mechanism that is not well understood, duplication mutations in the TNFRSF11A gene appear to overactivate the chemical signaling pathway that promotes osteoclast formation. The increased signaling stimulates the production of too many osteoclasts and triggers these cells to break down bone abnormally. In people with early-onset Paget disease of bone, affected bone is broken down and replaced much faster than usual. When the new bone tissue grows, it is weaker and less organized than normal bone. These problems with bone remodeling cause certain bones to become unusually large, misshapen, and easily broken (fractured).

other disorders - caused by mutations in the TNFRSF11A gene

Mutations in the TNFRSF11A gene are responsible for several other rare bone diseases, including two very similar disorders called familial expansile osteolysis (FEO) and expansile skeletal hyperphosphatasia (ESH). These disorders have signs and symptoms that overlap with those of early-onset Paget disease of bone. In fact, some researchers believe that FEO, ESH, and early-onset Paget disease of bone actually may be slightly different forms of a single condition. FEO and ESH both appear early in life and are characterized by skeletal abnormalities, tooth loss, and progressive hearing loss.

Like early-onset Paget disease of bone, FEO and ESH result from duplication mutations in the TNFRSF11A gene. Studies suggest that these mutations overactivate RANK, leading it to stimulate the production of too many osteoclasts and trigger these cells to break down bone abnormally. The resulting imbalance in bone remodeling causes the major features of these disorders. It is unclear why duplication mutations in the TNFRSF11A gene can cause several different bone diseases.

TNFRSF11A gene mutations also cause a bone disease called autosomal recessive osteopetrosis (ARO). This disorder appears in infancy and is characterized by abnormally dense bones. The increased bone density leads to a variety of complications, including an increased risk of fractures, vision impairment, hearing loss, and problems with the immune system related to defective bone marrow. Mutations in the TNFRSF11A gene appear to be a very rare cause of ARO; fewer than 10 mutations have been found in affected individuals. Most of these mutations change single amino acids in the RANK protein, which prevents it from receiving signals on the surface of immature osteoclasts. As a result, people with this condition have a total absence of mature, functional osteoclasts. Without these specialized cells to break down bone tissue, excess bone is formed throughout the skeleton.

Where is the TNFRSF11A gene located?

Cytogenetic Location: 18q22.1

Molecular Location on chromosome 18: base pairs 62,325,286 to 62,387,709

The TNFRSF11A gene is located on the long (q) arm of chromosome 18 at position 22.1.

The TNFRSF11A gene is located on the long (q) arm of chromosome 18 at position 22.1.

More precisely, the TNFRSF11A gene is located from base pair 62,325,286 to base pair 62,387,709 on chromosome 18.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about TNFRSF11A?

You and your healthcare professional may find the following resources about TNFRSF11A helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the TNFRSF11A gene or gene products?

  • CD265
  • FEO
  • ODFR
  • OFE
  • OPTB7
  • osteoclast differentiation factor receptor
  • OSTS
  • PDB2
  • RANK
  • receptor activator of NF-kappa-B
  • receptor activator of nuclear factor-kappa B
  • TNR11_HUMAN
  • TRANCER
  • tumor necrosis factor receptor superfamily, member 11a
  • tumor necrosis factor receptor superfamily, member 11a, activator of NFKB

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding TNFRSF11A?

acids ; autosomal ; autosomal recessive ; bone density ; bone marrow ; bone remodeling ; differentiation ; duplication ; familial ; gene ; immune system ; necrosis ; osteoclast ; protein ; receptor ; recessive ; tissue ; tumor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Elahi E, Shafaghati Y, Asadi S, Absalan F, Goodarzi H, Gharaii N, Karimi-Nejad MH, Shahram F, Hughes AE. Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation. J Bone Miner Metab. 2007;25(3):159-64. Epub 2007 Apr 20. (http://www.ncbi.nlm.nih.gov/pubmed/17447113?dopt=Abstract)
  • Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP, Helfrich MH, Crockett JC, Mellis D, Vellodi A, Tezcan I, Notarangelo LD, Rogers MJ, Vezzoni P, Villa A, Frattini A. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet. 2008 Jul;83(1):64-76. doi: 10.1016/j.ajhg.2008.06.015. (http://www.ncbi.nlm.nih.gov/pubmed/18606301?dopt=Abstract)
  • Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet. 2000 Jan;24(1):45-8. (http://www.ncbi.nlm.nih.gov/pubmed/10615125?dopt=Abstract)
  • Johnson-Pais TL, Singer FR, Bone HG, McMurray CT, Hansen MF, Leach RJ. Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. J Bone Miner Res. 2003 Feb;18(2):376-80. (http://www.ncbi.nlm.nih.gov/pubmed/12568416?dopt=Abstract)
  • Ke YH, Yue H, He JW, Liu YJ, Zhang ZL. Early onset Paget's disease of bone caused by a novel mutation (78dup27) of the TNFRSF11A gene in a Chinese family. Acta Pharmacol Sin. 2009 Aug;30(8):1204-10. doi: 10.1038/aps.2009.90. Epub 2009 Jul 6. (http://www.ncbi.nlm.nih.gov/pubmed/19578385?dopt=Abstract)
  • Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S, Elliott R, Scully S, Van G, Kaufman S, Juan SC, Sun Y, Tarpley J, Martin L, Christensen K, McCabe J, Kostenuik P, Hsu H, Fletcher F, Dunstan CR, Lacey DL, Boyle WJ. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1566-71. (http://www.ncbi.nlm.nih.gov/pubmed/10677500?dopt=Abstract)
  • Nakatsuka K, Nishizawa Y, Ralston SH. Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J Bone Miner Res. 2003 Aug;18(8):1381-5. (http://www.ncbi.nlm.nih.gov/pubmed/12929927?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/8792)
  • Palenzuela L, Vives-Bauza C, Fernández-Cadenas I, Meseguer A, Font N, Sarret E, Schwartz S, Andreu AL. Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene. J Med Genet. 2002 Oct;39(10):E67. (http://www.ncbi.nlm.nih.gov/pubmed/12362049?dopt=Abstract)
  • Whyte MP, Hughes AE. Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J Bone Miner Res. 2002 Jan;17(1):26-9. (http://www.ncbi.nlm.nih.gov/pubmed/11771666?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: February 2010
Published: July 21, 2014