Genomes and Genes
neurofibromatosis 2 genes
Summary: Tumor suppressor genes located on the long arm of human chromosome 22. Mutation or loss of these genes causes NEUROFIBROMATOSIS 2.
- Papi L, De Vitis L, Vitelli F, Ammannati F, Mennonna P, Montali E, et al. Somatic mutations in the neurofibromatosis type 2 gene in sporadic meningiomas. Hum Genet. 1995;95:347-51 pubmed..The nine tumors with an altered NF2 gene also showed LOH for 22q markers. These results further support the hypothesis that mutations in the NF2 gene are a critical pathogenetic event in at least some meningiomas. ..
- Evans D, Wallace A, Wu C, Trueman L, Ramsden R, Strachan T. Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis. Am J Hum Genet. 1998;63:727-36 pubmed..Degrees of gonosomal mosaicism mean that recurrence risks may well be <50% in the index case when a mutation is not identified in lymphocyte DNA. ..
- MacCollin M, Ramesh V, Jacoby L, Louis D, Rubio M, Pulaski K, et al. Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet. 1994;55:314-20 pubmed..A single patient carried a 3-bp deletion removing a phenylalanine residue. We conclude that the majority of NF2 patients carry an inactivating mutation of the NF2 gene and that neutral polymorphism in the gene is rare. ..
- Evans D, Ramsden R, Shenton A, Gokhale C, Bowers N, Huson S, et al. What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors?. J Neurosurg. 2008;108:92-6 pubmed publisher..Transmission risks are reduced for offspring, particularly in the older patients who are likely to be mosaic. ..
- Warren C, James L, Ramsden R, Wallace A, Baser M, Varley J, et al. Identification of recurrent regions of chromosome loss and gain in vestibular schwannomas using comparative genomic hybridisation. J Med Genet. 2003;40:802-6 pubmed..The GTPase signalling molecules RhoA and Rac1 regulate merlin function, but to date only mutation in the NF2 gene has been identified as a causal event in schwannoma formation...
- den Bakker M, van Tilborg A, Kros J, Zwarthoff E. Truncated NF2 proteins are not detected in meningiomas and schwannomas. Neuropathology. 2001;21:168-73 pubmed..From two tumors no protein was precipitated. Truncated NF2 proteins were not observed. The authors conclude that mutant NF2 proteins are unstable and undergo accelerated degradation. ..
- Ahronowitz I, Xin W, Kiely R, Sims K, MacCollin M, Nunes F. Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat. 2007;28:1-12 pubmed
- Evans D, Maher E, Baser M. Age related shift in the mutation spectra of germline and somatic NF2 mutations: hypothetical role of DNA repair mechanisms. J Med Genet. 2005;42:630-2 pubmed..This pattern is consistent with an age related decline in the efficiency of DNA repair mechanisms. Similar studies for other familial cancer genes may provide further evidence for this hypothesis. ..
- Kehrer Sawatzki H, Udart M, Krone W, Baden R, Fahsold R, Thomas G, et al. Mutational analysis and expression studies of the neurofibromatosis type 2 (NF2) gene in a patient with a ring chromosome 22 and NF2. Hum Genet. 1997;100:67-74 pubmed..The instability of the ring chromosome 22 with the associated loss of tumor suppressor genes on chromosome 22, in particular the loss of the NF2 gene, are assumed to have caused multiple tumorigenesis in this patient...
- Hansson C, Ali H, Bruder C, Fransson I, Kluge S, Andersson B, et al. Strong conservation of the human NF2 locus based on sequence comparison in five species. Mamm Genome. 2003;14:526-36 pubmed publisher..These elements could be affected by disease-causing mutations in NF2 patients and NF2-associated tumors. Alternatively, this conservation might be explained by presence of not yet characterized transcriptional unit(s) within this locus...
- Lomas J, Bello M, Arjona D, Alonso M, Martinez Glez V, Lopez Marin I, et al. Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas. Genes Chromosomes Cancer. 2005;42:314-9 pubmed..These results indicate that aberrant NF2 hypermethylation may participate in the development of a significant proportion of sporadic meningiomas, primarily those of grade I. ..
- Rouleau G, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 1993;363:515-21 pubmed..Its deduced product has homology with proteins at the plasma membrane and cytoskeleton interface, a previously unknown site of action of tumour suppressor genes in humans. ..
- Ruttledge M, Sarrazin J, Rangaratnam S, Phelan C, Twist E, Merel P, et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet. 1994;6:180-4 pubmed..These results provide strong evidence that the suppressor gene on chromosome 22, frequently inactivated in meningioma, is the NF2 gene, and suggest that another gene is involved in the development of 40% of meningiomas. ..
- Kino T, Takeshima H, Nakao M, Nishi T, Yamamoto K, Kimura T, et al. Identification of the cis-acting region in the NF2 gene promoter as a potential target for mutation and methylation-dependent silencing in schwannoma. Genes Cells. 2001;6:441-54 pubmed..Suppressed expression by aberrant methylation or mutation of the promoter elements could be an alternative mechanism for inactivation of the NF2 gene. ..
- Teo C, Nakaji P, Symons P, Tobias V, Cohn R, Smee R. Ependymoma. Childs Nerv Syst. 2003;19:270-85 pubmed..This review article examines the current status of histopathological and cytogenetic diagnosis, surgical, chemotherapeutic and radiotherapeutic treatment and future directions. ..
- Schmucker B, Tang Y, Kressel M. Novel alternatively spliced isoforms of the neurofibromatosis type 2 tumor suppressor are targeted to the nucleus and cytoplasmic granules. Hum Mol Genet. 1999;8:1561-70 pubmed..Although the NF2 protein is known as a cytoskeletal linker, additional functions in a cytoplasmic compartment and in the nucleus may exist. ..
- Hamaratoglu F, Willecke M, Kango Singh M, Nolo R, Hyun E, Tao C, et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2006;8:27-36 pubmed..Our genetic and biochemical data place Merlin and Expanded upstream of Hippo and identify a pathway through which they act as tumour-suppressor genes. ..
- Gutmann D, Hirbe A, Haipek C. Functional analysis of neurofibromatosis 2 (NF2) missense mutations. Hum Mol Genet. 2001;10:1519-29 pubmed..These results suggest that the key functional domains of merlin lie within the highly conserved FERM domain and the unique C-terminus of the protein. ..
- Pulst S, Riccardi V, Fain P, Korenberg J. Familial spinal neurofibromatosis: clinical and DNA linkage analysis. Neurology. 1991;41:1923-7 pubmed..Families such as these, in which a defined subset of the NF phenotype is passed on, are important for understanding the functional consequences of particular mutations in the NF genes. ..
- Jannatipour M, Dion P, Khan S, Jindal H, Fan X, Laganiere J, et al. Schwannomin isoform-1 interacts with syntenin via PDZ domains. J Biol Chem. 2001;276:33093-100 pubmed..Together, these results provide the first functional clue to the existence of schwannomin isoforms and could unravel novel pathways for the transport and subcellular localization of schwannomin in vivo. ..
- Zohar R, Suzuki N, Suzuki K, Arora P, Glogauer M, McCulloch C, et al. Intracellular osteopontin is an integral component of the CD44-ERM complex involved in cell migration. J Cell Physiol. 2000;184:118-30 pubmed..These studies indicate that OPN exists as an integral component of a hyaluronan-CD44-ERM attachment complex that is involved in the migration of embryonic fibroblasts, activated macrophages, and metastatic cells. ..
- Gusella J, Ramesh V, MacCollin M, Jacoby L. Merlin: the neurofibromatosis 2 tumor suppressor. Biochim Biophys Acta. 1999;1423:M29-36 pubmed..Consequently, the disruptions due to merlin inactivation in the progression of malignant mesothelioma may represent a tumor suppressor role operating by a different pathway than that in schwannoma or meningioma. ..
- Evans D. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. 2009;4:16 pubmed publisher..In the future, the development of tailored drug therapies aimed at the genetic level are likely to provide huge improvements for this devastating condition...
- Scoles D, Baser M, Pulst S. A missense mutation in the neurofibromatosis 2 gene occurs in patients with mild and severe phenotypes. Neurology. 1996;47:544-6 pubmed..This mutation was previously reported in an unrelated family in which all affected individuals had mild phenotypes. These data demonstrate a lack of correlation between NF2 genotype and NF2 phenotype for this mutation. ..
- Claudio J, Lutchman M, Rouleau G. Widespread but cell type-specific expression of the mouse neurofibromatosis type 2 gene. Neuroreport. 1995;6:1942-6 pubmed..In non-neuronal tissues immunostaining showed expression in cells of the tunica intima of blood vessels. We conclude that there is a widespread but cell type-specific expression of schwannomin. ..
- Fisher L, Doherty J, Lev M, Slattery W. Concordance of bilateral vestibular schwannoma growth and hearing changes in neurofibromatosis 2: neurofibromatosis 2 natural history consortium. Otol Neurotol. 2009;30:835-41 pubmed publisher..To examine the relationship between the amount of change in size and associated hearing in bilateral vestibular schwannomas (VSs) in persons with neurofibromatosis 2 (NF2)...
- Díaz de Ståhl T, Hansson C, De Bustos C, Mantripragada K, Piotrowski A, Benetkiewicz M, et al. High-resolution array-CGH profiling of germline and tumor-specific copy number alterations on chromosome 22 in patients affected with schwannomas. Hum Genet. 2005;118:35-44 pubmed..This association implicates these unstable regions in rearrangements occurring both in meiosis and mitosis. ..
- Lepont P, Stickney J, Foster L, Meng J, Hennigan R, Ip W. Point mutation in the NF2 gene of HEI-193 human schwannoma cells results in the expression of a merlin isoform with attenuated growth suppressive activity. Mutat Res. 2008;637:142-51 pubmed..These results indicate that, although HEI-193 cells have undetectable levels of merlin isoforms 1 and 2, they are, in fact, not a merlin-null model because they express the moderately active growth suppressive merlin isoform 3. ..
- Fisher L, Doherty J, Lev M, Slattery W. Distribution of nonvestibular cranial nerve schwannomas in neurofibromatosis 2. Otol Neurotol. 2007;28:1083-90 pubmed..Fortunately, neuropathies associated with these tumors are rare. In contrast, lower cranial nerve schwannomas, although also rare, are associated with swallowing difficulty, aspiration, and other sequelae. ..
- Baser M, Mautner V, Parry D, Evans D. Methodological issues in longitudinal studies: vestibular schwannoma growth rates in neurofibromatosis 2. J Med Genet. 2005;42:903-6 pubmed..Clinical trials for VS in NF2 should focus on younger patients because VS growth rates tend to decrease with increasing age, and because faster growing VS are more likely to be excised with increasing age than slower growing VS. ..
- Arai E, Ikeuchi T, Karasawa S, Tamura A, Yamamoto K, Kida M, et al. Constitutional translocation t(4;22) (q12;q12.2) associated with neurofibromatosis type 2. Am J Med Genet. 1992;44:163-7 pubmed..Several explanations are offered for the different expression of the translocation between the patient and her father. ..
- Selvanathan S, Shenton A, Ferner R, Wallace A, Huson S, Ramsden R, et al. Further genotype--phenotype correlations in neurofibromatosis 2. Clin Genet. 2010;77:163-70 pubmed publisher..Therefore patients with this class of NF2 mutation should be followed up closely...
- Gautreau A, Manent J, Fievet B, Louvard D, Giovannini M, Arpin M. Mutant products of the NF2 tumor suppressor gene are degraded by the ubiquitin-proteasome pathway. J Biol Chem. 2002;277:31279-82 pubmed..Altogether these results suggest that degradation of mutant Sch mediated by the ubiquitin-proteasome pathway is a physiopathological pathway contributing to the loss of Sch function in NF2 patients. ..
- Schipper H, Papp T, Johnen G, Pemsel H, Bastrop R, Muller K, et al. Mutational analysis of the nf2 tumour suppressor gene in three subtypes of primary human malignant mesotheliomas. Int J Oncol. 2003;22:1009-17 pubmed..Simultaneous comparative genomic hybridisation (CGH) analysis also showed losses at chromosome 22q. Our data indicate that functional loss of the NF2 protein may be involved in the formation of a subset of HMMs. ..
- Shaw R, McClatchey A, Jacks T. Localization and functional domains of the neurofibromatosis type II tumor suppressor, merlin. Cell Growth Differ. 1998;9:287-96 pubmed..Thus, as has been described for the erzin, radixin, and moesin proteins, the activities of the carboxyl-terminal domain of merlin may be suppressed by the amino-terminal domain. ..
- Tran Y, Bogler O, Gorse K, Wieland I, Green M, Newsham I. A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer. Cancer Res. 1999;59:35-43 pubmed..1 superfamily including ezrin and NF2. The data suggest DAL-1 is a novel membrane-associated protein with potential to play an important role in the origin and progression of lung cancer. ..
- Jacoby L, MacCollin M, Parry D, Kluwe L, Lynch J, Jones D, et al. Allelic expression of the NF2 gene in neurofibromatosis 2 and schwannomatosis. Neurogenetics. 1999;2:101-8 pubmed
- Sainz J, Huynh D, Figueroa K, Ragge N, Baser M, Pulst S. Mutations of the neurofibromatosis type 2 gene and lack of the gene product in vestibular schwannomas. Hum Mol Genet. 1994;3:885-91 pubmed..These data indicate that loss of NF2 protein function is a necessary step in schwannoma pathogenesis and that the NF2 gene functions as a recessive tumor suppressor gene. ..
- Wallace A, Wu C, Elles R. Meta-PCR: a novel method for creating chimeric DNA molecules and increasing the productivity of mutation scanning techniques. Genet Test. 1999;3:173-83 pubmed..Meta-PCR is likely to be useful to clinical molecular diagnostic laboratories, helping them to fulfill demand for rapid and accurate screening for point mutations in large multi-exon genes. ..
- Kluwe L, Mautner V, Parry D, Jacoby L, Baser M, Gusella J, et al. The parental origin of new mutations in neurofibromatosis 2. Neurogenetics. 2000;3:17-24 pubmed..A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations. ..
- Uhlmann E, Gutmann D. Tumor suppressor gene regulation of cell growth: recent insights into neurofibromatosis 1 and 2 gene function. Cell Biochem Biophys. 2001;34:61-78 pubmed..The neurofibromatosis 1 and neurofibromatosis 2 genes are discussed as illustrative examples of tumor suppressors that function at the levels of signal ..
- Kaufmann D, Leistner W, Kruse P, Kenner O, Hoffmeyer S, Hein C, et al. Aberrant splicing in several human tumors in the tumor suppressor genes neurofibromatosis type 1, neurofibromatosis type 2, and tuberous sclerosis 2. Cancer Res. 2002;62:1503-9 pubmed..Therefore, we suggest that the increase in aberrant splicing caused by environmental factors represents an additional mechanism for the reduction of the amount of tumor suppressor mRNA in the absence of relevant mutations in the tumor. ..
- Ruttledge M, Rouleau G. Role of the neurofibromatosis type 2 gene in the development of tumors of the nervous system. Neurosurg Focus. 2005;19:E6 pubmed..The authors describe some of the most significant findings in NF2 genetics and biology over the last decade. ..
- Governale L, Vortmeyer A, Zhuang Z, Oldfield E. Fibrous meningioma in a patient with von Hippel-Lindau disease: a genetic analysis. J Neurosurg. 2001;95:1045-9 pubmed..Given the high frequency of neuroimaging sessions in patients with VHL disease, some supratentorial lesions that have been given radiological diagnoses of hemangioblastomas may be incidental meningiomas. ..
- Kluwe L, Friedrich R, Hagel C, Lindenau M, Mautner V. Mutations and allelic loss of the NF2 gene in neurofibromatosis 2-associated skin tumors. J Invest Dermatol. 2000;114:1017-21 pubmed..We also report that the detection rate of constitutional mutations was higher in patients with skin tumors (65%) than in patients without skin tumors (40%). ..
- von Deimling A, Larson J, Wellenreuther R, Stangl A, van Velthoven V, Warnick R, et al. Clonal origin of recurrent meningiomas. Brain Pathol. 1999;9:645-50 pubmed..Our data should alert to the potential of meningioma cells for seeding during surgical procedures. ..
- van Tilborg A, Al Allak B, Velthuizen S, de Vries A, Kros J, Avezaat C, et al. Chromosomal instability in meningiomas. J Neuropathol Exp Neurol. 2005;64:312-22 pubmed..Thus, we conclude that even a benign and slow-growing tumor like a meningioma displays chromosomal instability. ..
- Diebold R, Bartelt Kirbach B, Evans D, Kaufmann D, Hanemann C. Sensitive detection of deletions of one or more exons in the neurofibromatosis type 2 (NF2) gene by multiplexed gene dosage polymerase chain reaction. J Mol Diagn. 2005;7:97-104 pubmed..Our gene dosage assay will detect deletions of one or more exons as well as gross deletions of the whole coding region of the gene. It can complement the existing screening methods because it is faster and easier. ..
- Gutmann D, Giovannini M. Mouse models of neurofibromatosis 1 and 2. Neoplasia. 2002;4:279-90 pubmed..Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors. ..
- Feucht M, Kluwe L, Mautner V, Richard G. Correlation of nonsense and frameshift mutations with severity of retinal abnormalities in neurofibromatosis 2. Arch Ophthalmol. 2008;126:1376-80 pubmed publisher..Clinical Relevance Retinal abnormalities, which can be revealed by means of fluorescein angiography, are more common in patients with NF2 who have nonsense or frameshift mutations. ..
- Englefield P, Foulkes W, Campbell I. Loss of heterozygosity on chromosome 22 in ovarian carcinoma is distal to and is not accompanied by mutations in NF2 at 22q12. Br J Cancer. 1994;70:905-7 pubmed..LOH data support this conclusion and that the putative tumour-suppressor gene lies distal to NF2, beyond D22S283. ..
- Fass G, Hossey D, Nyst M, Smets D, Saligheh E, Duttmann R, et al. Benign retroperitoneal schwannoma presenting as colitis: a case report. World J Gastroenterol. 2007;13:5521-4 pubmed..Schwannomatosis and NF2 should be excluded through clinical diagnostic criteria. Genetic testing of NF2 is probably not justified in the presence of a solitary retroperitoneal schwannoma. ..
- Murray A, Hughes T, Neal J, Howard E, Evans D, Harper P. A case of multiple cutaneous schwannomas; schwannomatosis or neurofibromatosis type 2?. J Neurol Neurosurg Psychiatry. 2006;77:269-71 pubmed..An identical point mutation in the NF2 gene in the two anatomically distinct tumours was found, confirming this as a case of NF2 mosaicism. ..