Neurofibromatosis type 2 (neurofibromatosis type 2) - NF2 Gene

Neurofibromatosis type 2 syndrome is an inherited predisposition to develop tumors in the nervous system. It is a very heterogeneous entity, even among hereditary familial cases, and unlike neurofibromatosis type 1 is rare (1 case in 25,000-35,000 individuals). It is characterized by the development of multiple schwannomas, meningiomas and ependymomas with associated symptoms of tinnitus, hearing loss and loss of balance. Despite being benign, most of these tumors have very harmful effects on cranial structures and the spinal column due to compression of nerves and brain. These disturbances generate diversity of symptoms and are the cause of the high heterogeneity of the syndrome. Complications of tumor growth may include changes in vision, numbness or weakness in the arms or legs, and accumulation of fluid in the brain. Some people with type 2 neurofibromatosis also develop cataracts in one or both eyes.

This process is due to genetic alterations in NF2, located on the long arm of chromosome 22 (22q12). This gene spans over 100 kb and approximately consists of 17 exons subject to alternative splicing. The NF2 gene encodes a protein called merlin (or schwannamina), whose major isoforms, 1 and 2 are composed of 595 and 590 amino acids respectively. This is similar to some members of ERM (Ezrin, Radixin, Moesin) protein, which is a family of proteins thought that link cytoskeletal components with proteins of the cell membrane, although so far it is the only this protein family involved in tumor suppression. In fact, the intervention has been shown of the merlin protein in the interaction with cell surface, with proteins involved in cytoskeletal dynamics and proteins involved in the regulation of ion transport. As to its function as a tumor suppressor, recent studies have shown their interaction in the nucleus with the E3 ubiquitin ligase and its contribution to the inhibition of the expression of genes involved in cell cycle progression and stimulation of gene expression involved in growth arrest and apoptosis.

There are more than 200 mutations in the NF2 gene in people with neurofibromatosis type 2. About 90% of the identified mutations result encoding a shortened version abnormally the merlin protein. This short protein can not perform its normal tumor suppressor function in cells. Because it is believed that the loss of merlin allows cells, especially Schwann cells, multiply and form too often noncancerous tumors. The most common tumors in neurofibromatosis type 2 are vestibular schwannomas that develop along the nerve that carries information from the inner ear to the brain. Other tumors affecting the nervous system also occur in people with this disease. Molecular diagnostics is especially important in cases such as neurofibromatosis type 2, where clinical criteria not provide sufficient certainty. In addition, molecular diagnosis allows early diagnosis, essential for effective therapy and improved living conditions of patients.

Neurofibromatosis type 2 is considered to have an autosomal dominant inheritance, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed. In about half of the cases, the altered gene is inherited from an affected parent. The remaining cases are due to new mutations in the NF2 gene and occur in people with no history of disease in your family. Unlike most other common autosomal dominant disorders in which an altered gene in each cell copy is sufficient to express a process, to be altered both copies of the NF2 gene to trigger the formation of a tumor in the neurofibromatosis type 2 . a mutation in the second copy of the NF2 gene can occur in Schwann cells or other cells in the nervous system during the life of a person. Almost all born with NF2 mutation acquires a second mutation (known as somatic mutation) in these cells and tumors develop characteristic of type 2 neurofibromatosis.

Tests in IVAMI: in IVAMI perform detection of mutations associated with neurofibromatosis type 2, by complete PCR amplification of the exons of the NF2 gene, 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) in case of detection of germline mutations; chorionic villus if prenatal diagnosis; or tissue from biopsy on detection of somatic mutations.