Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas

Hum Mutat. 2008 Feb;29(2):227-31. doi: 10.1002/humu.20679.


Schwannomatosis is characterized by the onset of multiple intracranial, spinal, or peripheral schwannomas, without involvement of the vestibular nerve, which is instead pathognomonic of neurofibromatosis type 2 (NF2). Recently, a schwannomatosis family with a germline mutation of the SMARCB1 gene on chromosome 22 has been described. We report on the molecular analysis of the SMARCB1 and NF2 genes in a series of 21 patients with schwannomatosis and in eight schwannomatosis-associated tumors from four different patients. A novel germline SMARCB1 mutation was found in one patient; inactivating somatic mutations of NF2, associated with loss of heterozygosity (LOH) of 22q, were found in two schwannomas of this patient. This is the second report of a germline SMARCB1 mutation in patients affected by schwannomatosis and the first report of SMARCB1 mutations associated with somatic NF2 mutations in schwannomatosis-associated tumors. The latter observation suggests that a four-hit mechanism involving the SMARCB1 and NF2 genes may be implicated in schwannomatosis-related tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Chromosomal Proteins, Non-Histone / genetics*
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Female
  • Humans
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • Neurilemmoma / genetics*
  • Neurofibromin 2 / genetics*
  • Peripheral Nervous System Neoplasms / genetics*
  • SMARCB1 Protein
  • Transcription Factors / genetics*


  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Neurofibromin 2
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors