Schwannomatosis (schwannomatosis) - Genes SMARCB1, LZTR1 and NF2

Schwannomatosis, also known as neurofibromatosis type 3, is a disorder characterized by the development of multiple benign tumors called schwannomas that develop on the nerves. Schwannomas develop when Schwann cells, which are specialized cells that normally form an insulating layer around the nerve, grow uncontrollably forming a tumor.

Signs and symptoms of schwannomatosis usually appear in early adulthood. The most common symptom is chronic pain, from mild to severe, which can affect any part of the body. In some cases, the pain is felt in areas where there are no tumors. Other signs and symptoms of schwannomatosis depend on the location of the tumor and the affected nerves. These problems include numbness, weakness, tingling and headaches. The life expectancy of people with schwannomatosis is normal.

Schwannomatosis is usually regarded as a form of neurofibromatosis, a group of disorders characterized by growth of tumors in the nervous system processes. The other two recognized forms of neurofibromatosis are neurofibromatosis type 1 and type 2 neurofibromatosis schwannomatosis characteristics can be very similar to those of the neurofibromatosis type 2. However, unlike type 2 neurofibromatosis, in persons with schwannomatosis rarely inner ear tumors known as vestibular schwannomas develop. Additional features of the other forms of neurofibromatosis, including the development of other types of tumors are much less frequent in schwannomatosis.

Schwannomatosis can be due to mutations in at least two genes, and LZTR1 SMARCB1. It is thought that the proteins encoded by both genes act as tumor suppressors, so that mutations in any of these genes may help cells to grow and divide uncontrollably. However, it appears that mutations in the gene SMARCB1 or LZTR1 alone are not sufficient to trigger the development of schwannomas. Certain additional genetic changes (somatic mutations) acquired during the life of a person and that are present only in certain cells may also be necessary for forming schwannomas. The most frequent mutations in schwannomas are somatic mutations of the NF2 gene and loss of chromosome 22, which is the chromosome on which are the SMARCB1, LZTR1 and NF2 gene.

The SMARCB1 (SWI / SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1), located on the long arm of chromosome 22 (22q11.23), encodes a subunit of several protein complexes SWI / SNF different. The SWI / SNF complexes regulate gene expression through chromatin remodeling to alter the way in which the DNA is assembled. The chromatin remodeling is a way to regulate gene expression during development. When DNA is strongly assembled, gene expression is lower than when the DNA is assembled more weakly. Through their ability to regulate gene activity, SWI / SNF complexes are involved in many processes, including DNA repair damaged DNA copy and the regulation of growth, division and cell differentiation. It is thought that the protein and other subunits SMARCB1 SWI / SNF act as tumor suppressors. However, the function of the protein SMARCB1 the SWI / SNF complex is not fully understood. They have identified more than two dozen mutations in the gene in people with SMARCB1 schwannomatosis. SMARCB1 mutations associated with schwannomatosis result in the synthesis of an altered protein SMARCB1 whose function is reduced, but not eliminated. Altered protein is less able to control growth and cell division, which may allow tumors to develop. However, it is unknown why these mutations are predominantly associated with schwannomas, rather than with other types of tumors.

The LZTR1 (leucine zipper transcription regulator like 1) gene, located on the long arm of chromosome 22 (22q11.21), encodes a protein in cells throughout the body whose precise function is unknown. Studies suggest that the protein LZTR1 can help stabilize the Golgi apparatus inside cells. In addition, it is believed that this protein may also be associated with the ubiquitin ligase complex Cul3, which is part of the cellular machinery that breaks unnecessary proteins. Based on its role in various tumors, it is thought that LZTR1 protein acts as a tumor suppressor. Described more than 50 mutations in the gene in people with LZTR1 schwannomatosis leading to the synthesis of an altered protein LZTR1 that is less able to control growth and cell division, allowing the development of tumors. It is not known why people with schwannomatosis these genetic mutations are predominantly associated with schwannomas, rather than with other types of tumor.

The NF2 (neurofibromin 2) gene, located on the long arm of chromosome 22 (22q12.2), encoding the merlin protein, also known as schwannomina. This protein is encoded in the nervous system, particularly in the Schwann cells that surround and insulate nerves. The merlin protein helps regulate several key signaling pathways that are important for controlling the shape, the growth and cell adhesion. This protein acts as a tumor suppressor, preventing cells from growing and dividing too fast or in an uncontrolled manner. Somatic mutations associated with schwannomatosis occur only in cells that give rise to tumors. It seems that these somatic mutations of the NF2 gene are not the cause of development of schwannomatosis although they are probably one of the genetic factors that contribute to tumor formation.

Some people with schwannomatosis not have a mutation identified in SMARCB1 or LZTR1 gene. In these cases, the cause of the disease is unknown. It is believed that mutations in other genes yet unidentified, most likely on chromosome 22 also contribute to the development of this process.

Most cases are sporadic schwannomatosis, meaning that occur in people with no history of disease in your family. Some people with sporadic schwannomatosis have mutations in the gene SMARCB1 or LZTR1, but in others, the cause of the disease is unknown. Studies suggest that between 15 and 25% of cases occur in families schwannomatosis. These familial cases have an autosomal dominant inheritance, meaning that a mutation in a copy of SMARCB1 or LZTR1 gene in each cell significantly increases the risk of developing schwannomas. However, some people who have an altered gene never develop tumors, a situation known as reduced penetrance.

Tests in IVAMI: in IVAMI perform detection of mutations associated with schwannomatosis, by complete PCR amplification of the exons of SMARCB1, LZTR1 and NF2, respectively, and subsequent sequencing genes.

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).