MUTATIONAL ANALYSIS OF PATIENTS WITH NEUROFIBROMATOSIS-2

Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the d evelopment of multiple nervous-system tumors in young adulthood. The N F2 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 affected in dividuals, we have used SSCP analysis to scan the exons of the NF2 gen e from 33 unrelated patients with NF2. Twenty unique SSCP variants wer e seen in 21 patients; 10 of these individuals were known to be the on ly affected person in their kindred, while 7 had at least one other kn own affected relative. In all cases in which family members were avail able, the SSCP variant segregated with the disease; comparison of spor adic cases with their parents confirmed the de novo variants. DNA sequ ence analysis revealed that 19 of the 20 variants observed are predict ed to lead to a truncated protein due to frameshift, creation of a sto p codon, or interference with normal RNA splicing. A single patient ca rried a 3-bp deletion removing a phenylalanine residue. We conclude th at the majority of NF2 patients carry an inactivating mutation of the NF2 gene and that neutral polymorphism in the gene is rare.