TNFRSF11A

MedlinePlus Genetics provides information about Osteopetrosis

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).

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.