title: Allelic expression of the NF2 gene in neurofibromatosis 2 and schwannomatosis.
abstract: Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by formation of multiple schwannomas and meningiomas due to inactivating mutations in the NF2 tumor suppressor gene on chromosome 22. We describe a polymorphism in the 3' untranslated region of the NF2 gene that is informative in about one-third of individuals. This polymorphism permitted an assessment of the relative expression of NF2 transcripts in lymphoblastoid cell RNA from 22 unrelated NF2 patients heterozygous for a germline NF2 mutation, along with 6 schwannomatosis patients, and 14 unaffected controls. Unequal allelic expression (1.8- to 20-fold) was detected in 15 of the NF2 cases, but in none of the schwannomatosis or control individuals. Underexpression of the NF2 mutant allele was documented for all 6 nonsense or frameshift mutations, 3 of 6 splice mutations, and 1 of 4 missense mutations, which, unexpectedly, was shown to alter the NF2 transcript and create a premature stop codon. In contrast, equal expression or slight overexpression of NF2 mutant alleles was observed for 2 in-frame deletions, 2 splice alterations, and 3 missense mutations. In the remaining 5 cases, the allele representing the mutant transcript was not known. Thus, truncating NF2 mutations, which are the most frequent alterations in NF2 patients and NF2-associated tumors, were associated with underexpression of the mutant allele, whereas the less common in-frame alterations usually showed normal or slight overexpression of the mutant transcript.
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA. jacoby@helix.mgh.harvard.edu
authors.forename: L B
authors.initials: LB
authors.lastname: Jacoby
authors.forename: M
authors.initials: M
authors.lastname: MacCollin
authors.forename: D M
authors.initials: DM
authors.lastname: Parry
authors.forename: L
authors.initials: L
authors.lastname: Kluwe
authors.forename: J
authors.initials: J
authors.lastname: Lynch
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: J F
authors.initials: JF
authors.lastname: Gusella
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22; D018388:Codon, Terminator; D016368:Frameshift Mutation; D016515:Genes, Neurofibromatosis 2; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008214:Lymphocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009442:Neurilemmoma / Q000235:genetics*; D016518:Neurofibromatosis 2 / Q000235:genetics*; D025581:Neurofibromin 2; D015183:Restriction Mapping; D017384:Sequence Deletion; D014158:Transcription, Genetic
chemical_list: D018388:Codon, Terminator; D008565:Membrane Proteins; D025581:Neurofibromin 2