Paget's Disease ... (Paget disease of bone) - Genes SQSTM1, TNFRSF11A and TNFRSF11B
Paget's disease is a disorder that causes bones to become larger and weaker than normal. Affected bones can deform and fracture easily.
The classic form of the disease usually occurs in middle age or later. It usually affects one or more bones without spread from one to another. Although the disease generally affects the bones of the spine, pelvis, skull or legs, it may be affected any bone. Many people with the classic form of the disease do not manifest symptoms associated with bone abnormalities. Often the disease is diagnosed unexpectedly by X - rays or laboratory tests performed for other reasons. People who develop symptoms are more likely to suffer pain. Affected bones can be painful or pain may be due to arthritis in nearby joints. In people with this disease, arthritis most often affects the knees and hips. Other complications of the disease depend on the affected bones. If the disease in the bones of the skull, may result in an elongated head, hearing loss, headache and dizziness. If the disease affects the bones of the spine, can lead to numbness and tingling due to nerve compression and abnormal curvature of the spine. In the bones of the legs, the disease can result in bowed legs and difficulty walking. Osteosarcoma, a rare bone cancer, has been associated with the disease. This type of cancer is likely to occur in less than 1 in 1,000 people with this disease.
A less common form of the disease, is how early or juvenile onset, which usually presents in adolescence or young adulthood. Its features are similar to those of the classical form of the disease, although it is more likely to affect the skull, spine and ribs as well as the small bones of the hands. The early onset form of the disease is also associated with hearing loss at an early age.
A combination of genetic and environmental factors may play a role in the development of Paget's disease of bone. Changes have been identified in several genes that increase the risk of disease. Other factors, including infection by certain viruses, may be involved in triggering the disease in people who are at risk. However, the influence of genetic and environmental factors in the development of the disease remains unclear.
Variations have been identified in three genes that are associated with this process: SQSTM1 (sequestosome 1), TNFRSF11A (tumor necrosis factor receptor superfamily member 11a) and TNFRSF11B (Tumor necrosis factor receptor superfamily member 11b). Mutations in the SQSTM1 gene are the most common genetic cause of Paget 's , which represents between 10 and disease 50% of cases occur in families and 5 to 30% of cases where no a family history of the disease. Variations in the gene TNFRSF11B also appear to increase the risk of classical form of the disease, particularly in women. Mutations in the TNFRSF11A gene lead to juvenile form of the disease.
The SQSTM1 gene (sequestosome 1), located on the long arm of chromosome 5 (5q35), encoding the p62 protein. This protein plays an important role in bone remodeling. The p62 protein helps regulate this process through its role in a signaling pathway that promotes chemical osteoclast formation. Studies suggest that p62 may have other functions besides its role in bone remodeling. It is believed to be involved in autophagy, apoptosis, and immune responses of the organism and inflammatory reactions. There are more than 20 mutations in the gene responsible for developing SQSTM1 Paget's disease bone. These mutations consist of amino acid changes in the p62 protein. The most frequent mutation replaces the amino acid proline in the amino acid leucine position 392 of the protein (Pro392Leu or P392L). Through a mechanism that is not well understood, SQSTM1 gene mutations appear overactivating chemical signaling pathway that promotes formation of osteoclasts, leading to the production of osteoclasts too and triggers these cells to break the abnormal bone. In those affected, the affected bone is broken down and is replaced much faster than usual. When the new bone tissue grows, it is weaker and less organized than normal bone. These problems cause certain bone remodeling bones to become unusually large, deformed, and break easily.
The TNFRSF11A gene (tumor necrosis factor receptor superfamily member 11a), located on the long arm of chromosome 18 (18q22.1), encoding the protein receptor activator of NF-kB (RANK). This protein plays an important role in bone remodeling. During bone remodeling, RANK helps direct the formation and function of osteoclasts, which break down bone tissue. RANK is found on the surface of mature osteoclasts, which receives signals that trigger these cells to mature and become functional. At least two very similar mutations have been identified in the TNFRSF11A gene in people with the classic form of the disease, particularly in women. However, mutations in this gene are responsible for early onset form. Both mutations are duplications, which means that abnormally copied a segment of genetic material into the gene. Each of these mutations results in the synthesis of a RANK protein containing several additional amino acids. Through a mechanism that is not well understood, the duplication mutations in the TNFRSF11A gene appear overactivating pathway signaling chemical that promotes osteoclast formation, which stimulates the production of an excess of osteoclasts and triggers these cells to decompose the bone abnormally. In affected individuals, affected bone decomposes and replaces much faster than usual, a weaker and less organized bone tissue.
The gene TNFRSF11B (Tumor necrosis factor receptor superfamily member 11b), located on the long arm of chromosome 8 (8q24), encoding osteoprotegerin protein. Osteoprotegerin is involved in the regulation of osteoclasts that break down bone during bone remodeling. Osteoprotegerin is one of two receptor proteins capable of binding to receptor activator NF-kB ligand (RANKL). The other receptor protein is the receptor activator of NF-KB (RANK), encoded from TNFRSF11A gene. When RANKL is bound to RANK, it starts a series of chemical signals that activate mature osteoclasts to become functional. When RANKL is attached to osteoprotegerin, blocks these chemical signals and inhibits activation of osteoclasts. By reducing the amount of RANKL that is available to bind to RANK, osteoprotegerin plays a critical role in regulating bone remodeling process. They have identified at least six mutations in the gene responsible for the development TNFRSF11B juvenile or early onset form. Each of these mutations greatly reduces the role of osteoprotegerin or inhibit the synthesis of this protein. No osteoprotegerin, RANKL binds only to RANK. As a result, an increase in chemical signaling stimulates the production of osteoclasts too and triggers these cells to break the bone abnormally occurs. In affected individuals, affected bone decomposes and replaces much faster than usual, a weaker and less organized bone tissue.
In most cases, the disease is an autosomal dominant inheritance, which means that have a copy of an altered gene in each cell is sufficient to express the disease. In other cases, it is unclear inheritance pattern of the disease. Many people affected have no family history of the disease. Studies suggest that close relatives of people with Paget disease of bone classical having 7 to 10 times more likely to develop the disease than people without an affected relative.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Paget's disease by the complete PCR amplification of the exons of SQSTM1 genes TNFRSF11A, TNFRSF11B and, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).