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The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2
  1. M E Baser1,
  2. L Kuramoto2,
  3. R Woods2,
  4. H Joe2,
  5. J M Friedman3,
  6. A J Wallace4,
  7. R T Ramsden5,
  8. S Olschwang6,
  9. E Bijlsma7,
  10. M Kalamarides8,
  11. L Papi9,
  12. R Kato10,
  13. J Carroll11,
  14. C Lázaro12,
  15. F Joncourt13,
  16. D M Parry14,
  17. G A Rouleau15,
  18. D G R Evans4
  1. 110622 Kinnard Ave, #203, Los Angeles, CA, USA
  2. 2Department of Statistics, University of British Columbia, Vancouver, BC, Canada
  3. 3Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
  4. 4University Department of Medical Genetics, St Mary’s Hospital, Manchester, UK
  5. 5Department of Otolaryngology, Manchester Royal Infirmary, Manchester, UK
  6. 6INSERM U434, Fondation Jean-Dausset-CEPH, Paris, France
  7. 7Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  8. 8Department of Neurosurgery, University Hospital Beaujon, Clichy, France
  9. 9Department of Clinical Physiopathology, University of Florence, Florence, Italy
  10. 10Department of Pediatrics, Higashisaitama National Hospital, Saitama, Japan
  11. 11Division of Molecular Pathology, Institute of Medical and Veterinary Science, Adelaide, Australia
  12. 12Centre de Genètica Mèdica i Molecular – I.R.O., L’Hospitalet de Llobregat, Barcelona, Spain
  13. 13Division of Human Genetics, Children’s University Hospital, Berne, Switzerland
  14. 14Genetic Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA
  15. 15Department of Neurology, McGill University, Montreal, QC, Canada
  1. Correspondence to:
 Dr Michael E Baser
 10622 Kinnard Ave, #203, Los Angeles, CA 90024;


Neurofibromatosis 2 (NF2) patients with constitutional splice site NF2 mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional NF2 mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1–5 had more severe disease than those with splice site mutations in exons 11–15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours.

  • genotype-phenotype correlation
  • neurofibromatosis 2
  • NF2
  • splice site mutation

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  • Supported in part by the FBT Foundation and US Army grant U.S.A.R.M.C. NF990038. CL was partially supported by grants from the Fondo de Investigaciones Sanitarias (FIS01/1475), the Ministerio de Educación y Ciencia (SAF2002-00573), the Institut Catala de la Salut (ISIII C03/07), and 2001SGR00399 from Generalitat de Catalunya, Spain.

  • Competing interests: none declared