title: Mild familial neurofibromatosis 2 associates with expression of merlin with altered COOH-terminus.
abstract: OBJECTIVE
  To understand molecular details of the pathogenesis of a very mild and homogenous form of neurofibromatosis 2 (NF2).
  
  
  BACKGROUND
  Inactivation of the NF2 tumor suppressor gene leads to the development of multiple nervous system tumors, accompanied by loss of the NF2 gene product, merlin, or schwannomin. The severity of disease varies between patients, and the biologic basis of this variation is poorly understood.
  
  
  METHODS
  We studied the genotype-phenotype correlation in a large pedigree with extremely mild and uniform disease manifesting as slowly growing bilateral vestibular nerve schwannomas of late onset.
  
  
  RESULTS
  The tumors demonstrated a low proliferation rate and loss of the wild-type NF2 allele. The disease is caused by a novel mutation in the NF2 gene at intron 15 splice donor site (1737 + 3 a --> t), which was identified in all carriers by the minisequencing method. The mutation resulted in splicing out of exon 15 and production of two transcripts: a novel mutant transcript with exon 16 and overexpression of isoform III, normally detected at a low level. Both transcripts encode for the COOH-terminus of isoform III. Immunoblotting of patient fibroblasts and tumor tissue demonstrated variant merlin with altered COOH-terminus.
  
  
  CONCLUSIONS
  The mutational skip of exon 15 and the expression of a protein with the COOH-terminus of isoform III correlates with the exceptionally mild NF2, and suggests tumor suppressor activity for isoform III. The detection of expressed mutant proteins may provide useful information for prediction of the clinical outcome of individual mutations.
authors.affiliation: Department of Neurology, University of Helsinki, Finland. markku.sainio@helsinki.fi
authors.forename: M
authors.initials: M
authors.lastname: Sainio
authors.forename: J
authors.initials: J
authors.lastname: Jääskeläinen
authors.forename: H
authors.initials: H
authors.lastname: Pihlaja
authors.forename: O
authors.initials: O
authors.lastname: Carpén
mesh_terms: D000483:Alleles; D005091:Exons; D016515:Genes, Neurofibromatosis 2 / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D019656:Loss of Heterozygosity; D008565:Membrane Proteins / Q000032:analysis*; D009154:Mutation / Q000235:genetics; D016518:Neurofibromatosis 2 / Q000235:genetics*; D025581:Neurofibromin 2; D010375:Pedigree; D010641:Phenotype
chemical_list: D008565:Membrane Proteins; D025581:Neurofibromin 2