Molecular pathogenesis of the schwannomatosis genes and genetic testing strategies

Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, International Consensus Group on Neurofibromatosis Diagnostic C, Yohay K, Huson SM, Wolkenstein P, Evans DG (2022) Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med 24:1967–1977

Article  CAS  PubMed  Google Scholar 

Forde C, Smith MJ, Burghel GJ, Bowers N, Roberts N, Lavin T, Halliday J, King AT, Rutherford S, Pathmanaban ON, Lloyd S, Freeman S, Halliday D, Parry A, Axon P, Buttimore J, Afridi S, Obholzer R, Laitt R, Thomas O, Stivaros SM, Vassallo G, Evans DG (2024) NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study. J Med Genet 61:856–860

Article  CAS  PubMed  Google Scholar 

Merker VL, Esparza S, Smith MJ, Stemmer-Rachamimov A, Plotkin SR (2012) Clinical features of schwannomatosis: a retrospective analysis of 87 patients. Oncologist 17:1317–1322

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jordan JT, Smith MJ, Walker JA, Erdin S, Talkowski ME, Merker VL, Ramesh V, Cai W, Harris GJ, Bredella MA, Seijo M, Suuberg A, Gusella JF, Plotkin SR (2018) Pain correlates with germline mutation in schwannomatosis. Medicine (Baltimore) 97:e9717

Article  CAS  PubMed  Google Scholar 

Rubright R, Caterina MJ, Belzberg A, Ostrow KL (2025) Conditioned medium from painful non-NF2 schwannomatosis tumors increases pain behaviors in mice. Sci Rep 15:15851

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ostrow KL, Donaldson KJ, Caterina MJ, Belzberg A, Hoke A (2019) The secretomes of painful versus nonpainful human schwannomatosis tumor cells differentially influence sensory neuron gene expression and sensitivity. Sci Rep 9:13098

Article  PubMed  PubMed Central  Google Scholar 

Smith MJ, Wallace AJ, Bowers NL, Rustad CF, Woods CG, Leschziner GD, Ferner RE, Evans DG (2012) Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics 13:141–145

Article  CAS  PubMed  Google Scholar 

Smith MJ, Bowers NL, Bulman M, Gokhale C, Wallace AJ, King AT, Lloyd SK, Rutherford SA, Hammerbeck-Ward CL, Freeman SR, Evans DG (2017) Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology 88:87–92

Article  CAS  PubMed  PubMed Central  Google Scholar 

Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, Halpin C, Padera TP, Tyrrell A, Sorensen AG, Jain RK, di Tomaso E (2009) Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med 361:358–367

Article  CAS  PubMed  PubMed Central  Google Scholar 

Evans DG, Halliday D, Obholzer R, Afridi S, Forde C, Rutherford SA, Hammerbeck-Ward C, Lloyd SK, Freeman SM, Pathmanaban ON, Thomas OM, Laitt RD, Stivaros S, Kilday JP, Vassallo G, McBain C, Lavin T, Paterson C, Whitfield G, McCabe MG, Axon PR, Halliday J, Mackeith S, Parry A, English Specialist NFRG, Harkness EF, Buttimore J, King AT (2023) Radiation treatment of benign tumors in NF2-related-schwannomatosis: A national study of 266 irradiated patients showing a significant increase in malignancy/malignant progression. Neurooncol Adv 5:vdad025

PubMed  PubMed Central  Google Scholar 

Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K et al (1993) A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 75:826

CAS  PubMed  Google Scholar 

Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B et al (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:515–521

Article  CAS  PubMed  Google Scholar 

Sherman L, Xu HM, Geist RT, Saporito-Irwin S, Howells N, Ponta H, Herrlich P, Gutmann DH (1997) Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene 15:2505–2509

Article  CAS  PubMed  Google Scholar 

Turunen O, Sainio M, Jaaskelainen J, Carpen O, Vaheri A (1998) Structure-function relationships in the ezrin family and the effect of tumor-associated point mutations in neurofibromatosis 2 protein. Biochim Biophys Acta 1387:1–16

Article  CAS  PubMed  Google Scholar 

Kang BS, Cooper DR, Devedjiev Y, Derewenda U, Derewenda ZS (2002) The structure of the FERM domain of merlin, the neurofibromatosis type 2 gene product. Acta Crystallogr D Biol Crystallogr 58:381–391

Article  PubMed  Google Scholar 

Meng JJ, Lowrie DJ, Sun H, Dorsey E, Pelton PD, Bashour AM, Groden J, Ratner N, Ip W (2000) Interaction between two isoforms of the NF2 tumor suppressor protein, merlin, and between merlin and ezrin, suggests modulation of ERM proteins by merlin. J Neurosci Res 62:491–502

Article  CAS  PubMed  Google Scholar 

Hennigan RF, Thomson CS, Stachowski K, Nassar N, Ratner N (2023) Merlin tumor suppressor function is regulated by PIP2-mediated dimerization. PLoS ONE 18:e0281876

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gutmann DH, Haipek CA, Hoang Lu K (1999) Neurofibromatosis 2 tumor suppressor protein, merlin, forms two functionally important intramolecular associations. J Neurosci Res 58:706–716

Article  CAS  PubMed  Google Scholar 

Baser ME, Kuramoto L, Joe H, Friedman JM, Wallace AJ, Gillespie JE, Ramsden RT, Evans DG (2004) Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. Am J Hum Genet 75:231–239

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kluwe L, Bayer S, Baser ME, Hazim W, Haase W, Funsterer C, Mautner VF (1996) Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes. Hum Genet 98:534–538

Article  CAS  PubMed  Google Scholar 

Ahronowitz I, Xin W, Kiely R, Sims K, MacCollin M, Nunes FP (2007) Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat 28:1–12

Article  CAS  PubMed  Google Scholar 

Smith MJ, Higgs JE, Bowers NL, Halliday D, Paterson J, Gillespie J, Huson SM, Freeman SR, Lloyd S, Rutherford SA, King AT, Wallace AJ, Ramsden RT, Evans DG (2011) Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset. J Med Genet 48:261–265

Article  CAS  PubMed  Google Scholar 

Hexter A, Jones A, Joe H, Heap L, Smith JM, Wallace JA, Halliday D, Parry A, Taylor A, Raymond L, Shaw A, Afridi S, Obholzer R, Axon P, King TA, Friedman MJ, Evans GD (2015) Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients. J Med Genet 52:699–705

Article  CAS  PubMed  Google Scholar 

Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ, Evans DG, Roberts AM, Quaife NM, Schafer S, Rackham O, Alfoldi J, O’Donnell-Luria AH, Francioli LC, Genome Aggregation Database Production T, Genome Aggregation Database C, Cook SA, Barton PJR, MacArthur DG, Ware JS (2020) Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals. Nat Commun 11:2523

Article  CAS  PubMed  PubMed Central  Google Scholar 

Olexiouk V, Crappe J, Verbruggen S, Verhegen K, Martens L, Menschaert G (2016) sORFs.org: a repository of small ORFs identified by ribosome profiling. Nucleic Acids Res 44:D324-329

Article  CAS  PubMed  Google Scholar 

Smith MJ, Urquhart JE, Harkness EF, Miles EK, Bowers NL, Byers HJ, Bulman M, Gokhale C, Wallace AJ, Newman WG, Evans DG (2016) The contribution of whole gene deletions and large rearrangements to the mutation spectrum in inherited tumor predisposing syndromes. Hum Mutat 37:250–256

Article  CAS  PubMed  Google Scholar 

De Raedt T, Brems H, Wolkenstein P, Vidaud D, Pilotti S, Perrone F, Mautner V, Frahm S, Sciot R, Legius E (2003) Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet 72:1288–1292

Article  CAS  PubMed  PubMed Central 

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