Neurofibromatosis 2 (NF2), also known as bilateral acoustic neurofibromatosis or central neurofibromatosis, is a severe autosomal dominant disease characterized by the development of multiple nervous system tumors. The tumors of NF2, which include schwannomas, meningiomas and ependymomas, are histologically benign; however, their location and multiplicity led to great morbidity and mortality. These tumors commonly affect the general population in their isolated form, and have been found to undergo loss of chromosome 22 material in many studies; because of this the NF2 gene has been postulated to be a classic tumor suppressor. The NF2 gene has recently been isolated and found to encode a new member of the protein 4.1 family of cytoskeletal associated proteins which we have named merlin. To define the molecular basis of NF2 in germline and tumor specimens, we have used single-stranded conformation polymorphism (SSCP) analysis to scan the exons of the NF2 gene. We have located and characterized underlying causative mutation in 21 of 33 unrelated affected individuals studied, and 32 of 38 schwannomas. DNA sequence analysis revealed that over 90% of NF2 mutations are predicted to lead to a truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing. Current studies focus on relating the highly variable NF2 phenotype to its genotype, defining alternative NF2 related phenotypes, and elucidating the parental origin of new mutation in this disease.