Understanding NF2 Clinical Variability
Posted May 18, 2005
Jan Dumanski, Ph.D., Uppsala University, Sweden

Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by the development of schwannomas and other nervous system tumors, although disease manifestations and severity differ widely among affected individuals. Dr. Jan Dumanski, a leader in the field of array-comparative genomic hybridization (CGH), a cutting-edge genetic analysis technology, has received two awards from the Neurofibromatosis Research Program to elucidate the mechanisms underlying NF2 clinical variability. His group found no correlations between specific deletions in the NF2 gene (also called merlin or schwannomin) and disease severity, suggesting that the observed variability may be caused by other genes, known as modifier genes, that affect NF2 symptom development. They hypothesize that the gene responsible for the development of schwannomatosis, a disease closely related to NF2, may be an NF2 modifier gene. A candidate schwannomatosis gene has been identified on the same chromosome as merlin, and further analysis of this gene is in progress. Other ongoing projects include (1) the identification of genes contributing to the development of NF2 ependymomas, meningiomas, and astrocytomas; (2) analysis of regulatory elements in the NF2 gene, which may control the timing, location, and amount of merlin protein produced; and (3) improvement of array-CGH methodology for the diagnosis of NF2. Dr. Dumanski's research will help improve understanding of the molecular mechanisms underlying NF2 and schwannomatosis and provide a foundation for the development of improved therapies for these disorders.


For additional information about this research, please refer to the following list of selected publications:

  • Bruder CE, Hirvela C, Tapia-Paez I, et al. 2001. High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH. Human Molecular Genetics 10:271-282.
  • Buckley PG, Jarbo C, Menzel U, et al. 2005. Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling-path microarray identifies novel candidate tumor suppressor loci. Cancer Research 65:2653-2661.
  • Buckley PG, Mantripragada KK, Benetkiewicz M, et al. 2002. A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. Human Molecular Genetics 11:3221-3229.
  • Buckley PG, Mantripragada KK, Piotrowski A, et al. Copy-number polymorphisms: Mining the tip of an iceberg. Trends in Genetics. (in press).
  • Dhami P, Coffey AJ, Abbs S, et al. 2005. Exon array CGH: Detection of copy-number changes at the resolution of individual exons in the human genome. American Journal of Human Genetics 76: 750-762.
  • Hansson CM, Ali H, Bruder CE, et al. 2003. Strong conservation of the human NF2 locus based on sequence comparison in five species. Mammalian Genome 14:526-536.
  • Mantripragada KK, Buckley PG, Benetkiewicz M, et al. 2003. High-resolution profiling of an 11 Mb segment of human chromosome 22 in sporadic schwannoma using array-CGH. International Journal of Oncology 22:615-622.
  • Mantripragada KK, Buckley PG, Diaz de Ståhl T, et al. 2004. Genomic microarrays in the spotlight. Trends in Genetics 20:87-94.
  • Mantripragada KK, Buckley PG, Jarbo C, et al. 2003. Development of NF2 gene specific, strictly sequence defined diagnostic microarray for deletion detection. Journal of Molecular Medicine 81:443-451.

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Phase II trials Underway for NF1 Treatment
Posted April 18, 2005
Roger Packer, M.D., Children's National Medical Center, Washington, DC

Individuals with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), tumors arising from the coverings of multiple nerves that can cause disfigurement and severe neurological impairment. There are no effective drugs available for the treatment of PNs, and complete surgical removal of the tumors is often impossible because of their large size. Pirfenidone is a novel oral anti-fibrotic agent that targets growth factors elevated in PNs, suggesting that this drug may inhibit PN development or growth. Dr. Roger Packer, a recipient of a Neurofibromatosis Research Program Clinical Trial Award, is conducting studies to assess the toxicity and effectiveness of pirfenidone in children with NF1 and progressive PNs. Recently completed Phase I safety trials revealed that pirfenidone is well tolerated in children and identified the optimal dose for pediatric patients. Phase II trials examining the effects of the drug on tumor progression and quality of life are about to begin. Since there are no effective therapies for progressive PNs other than surgery, Dr. Packer's research has the potential to greatly benefit many children with NF1.


Abstract: Phase I and Phase II Studies of Pirfenidone in Children with Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas

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Improving Ras-Targeted Treatment Approaches for NF1 Tumors
Posted March 29, 2005
David Gutmann, M.D., Ph.D., Washington University

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the formation of optic pathway gliomas and other nervous system tumors. Non-surgical therapies for NF1 tumors are greatly needed. Loss of the NF1 gene, neurofibromin, is associated with enhanced activation of growth-stimulating Ras proteins, suggesting that Ras inhibitors may impair NF1 tumor development. However, preliminary human studies with a class of Ras inhibitors known as farnesyltransferase inhibitors (FTIs) have been disappointing. The work of Dr. David Gutmann of Washington University, a recipient of a Neurofibromatosis Research Program Investigator-Initiated Research Award, provides a potential explanation for the relatively low effectiveness of FTIs in NF1 and identifies alternative Ras-targeted approaches that may be preferable for treating NF1 tumors. Dr. Gutmann used primary cell cultures as well as genetically-engineered Nf1 mutant mice to examine the roles of the three types (isoforms) of Ras proteins in the development of NF1 gliomas. Dr. Biplab Dasgupta, a post-doctoral fellow in his laboratory, found that Nf1 loss in astrocytes, nervous system cells that form gliomas, resulted in preferential activation of K-Ras, but not the other Ras isoforms. Activation of K-Ras in normal astrocytes mimicked the effects of Nf1 loss on cell growth and migration, and inhibition of K-Ras reversed the abnormalities observed in astrocytes lacking Nf1. Additionally, activation of K-Ras in astrocytes of Nf1+/- mice resulted in the formation of optic pathway gliomas, similar to Nf1+/- mice lacking Nf1 gene expression in astrocytes. These results suggest that K-Ras is the primary target for neurofibromin in astrocytes, and that excessive activation of K-Ras plays a critical role in the formation of NF1 gliomas. Importantly, FTIs are known to have minimal effects on K-Ras function, indicating that drugs specifically targeting K-Ras or proteins activated by K-Ras may be more effective for the treatment of NF1-associated brain tumors.


Dasgupta B, Li W, Perry A, and Gutmann DH. 2005. Glioma formation in neurofibromatosis 1 reflects preferential activation of K-RAS in astrocytes. Cancer Research 65:236-245.

Bajenaru ML, Hernandez MR, Perry A, et al. 2003. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Research 63:8573-8577.


Abstract: Modeling NF1-Associated Astrocytomas In Vitro and In Vivo

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A New Model for Merlin Localization and Function
Posted February 11, 2005
Wallace Ip, Ph.D., University of Cincinnati College of Medicine, Ohio

NF2, an inherited disorder that affects 1 in 40,000 individuals, is characterized by the formation of bilateral schwannoma of the 8th cranial nerve and predisposition to other nervous system tumors. NF2 is caused by mutations in a tumor suppressor gene called merlin, a member of a family of proteins that bind to the structural support network in cells (known as the cytoskeleton). Recent work by Dr. Wallace Ip at the University of Cincinnati College of Medicine, a recipient of an FY02 NFRP Idea Award, provides new insight into merlin localization and function. Dr. Ip's group demonstrated that most merlin within cells is attached to specialized areas of the cell membrane called lipid rafts. His data also suggest that merlin activation is accompanied by dissociation of merlin-containing lipid rafts from the cytoskeleton. Merlin is the first tumor suppressor to be localized to lipid rafts, which contain a high concentration of signaling molecules that regulate cell growth. These findings suggest that the ability of merlin to disrupt growth-promoting signaling pathways originating from the cell membrane may be dependent on its association with the rafts. Future studies will examine whether mutant merlin proteins modeled after mutations known in NF2 patients are defective in lipid raft targeting and whether forced localization of the mutant proteins to lipid rafts can restore normal function. Dr. Ip's research may provide explanations for the loss of function associated with some merlin mutations and ultimately help investigators develop new therapeutics for the affected individuals.


Stickney JT, Bacon WC, Rojas M, et al. 2004. Activation of the tumor suppressor merlin modulates its interaction with lipid rafts. Cancer Research 64:2717-2724.

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