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Neurofibromatosis Research at MGH

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Research has always been a major focus of the MGH NF clinic. For example, the positional cloning of the NF2 gene by the Neurogenetics Unit was made possible in large part because of the many clinic families who had generously donated samples to the lab over the years. Patients continue to take part in basic science research being done on both NF1 and NF2 at the Charlestown Navy Yard campus. Studies on the molecular basis of NF1, the functions of NF1 and NF2 proteins, the effects of genotype on phenotype in NF2 and the molecular basis of new mutation in these diseases are all dependent on the continued support of our patients and their families. An especially valuable resource is tumor specimens removed from these patients, such as schwannomas, meningiomas, neurofibromas and malignant tumors.

Current research projects include:

NF2 Mutation Maps (see also NF2 Map References):

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[ 2006 Constitutional Map 1-9.jpg | 2006 Constitutional Map 1-9.tif ]


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2006 Constitutional Map 10-17.jpg | 2006 Constittional Map 10-17.tif ]

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[ 2006 Somatic Map 10-17.jpg | 2006 Somatic Map10-17.tif ]

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NF2 Map notes (see also NF2 Map References):

The NF2 mutation map is now subdivided into two separate gene maps. The first is an expansion of the original NF2 map and includes all published constitutional alterations in the NF2 gene, defined as appearing in unaffected non-tumor tissue or in two anatomically and/or pathologically distinct tumors bearing the same genetic change. The second map is the new somatic mutation map, listing changes from normal genetic sequence that appear exclusively in tumor tissue (multiple meningioma mutations are considered somatic because they are thought to represent non-contiguous spread of a single tumor) and not in blood. These maps collectively represent all published NF2 mutations to date, as well as verified unpublished mutations found by our group.

Mutations are denoted according to the nomenclature of the Human Genome Variation Society (HGVS) as updated in July 2004, available online at <http://www.genomic.unimelb.edu.au/mdi/mutnomen/>. In general, the numbering of bases showing alteration is given relative to the cDNA sequence from Rouleau et al., 1993 with the initiator ATG beginning at base 1. All coding sequence bases are given in upper case. When the alteration affects introns it is numbered as '+" or "-" the number of bases from the first or last base of the nearest exon. Intronic sequence is given in lower case. Where the start positions of deletions or insertions are uncertain, the most 3’ possible affected base affected is given, according to HGVS convention. Finally, mutations with unknown first affected base are denoted by a range of possible basepairs in parentheses.

All mutations are listed by the reference in which they were first reported, even if phenotypic information was reported in subsequent work. Each reference given reports a single instance of the mutation, and thus a reference is cited once for each time a mutation appears. Mutations listed in black are truncating/splicing events reported in a single kindred or individual. Mutations listed in red are truncating/splicing events reported in multiple unrelated individuals. Mutations listed in green are non-truncating. Note that putative splicing events and non- truncating base changes may not have been confirmed to be pathogenic. Mutations felt to be non-pathogenic benign polymorphisms are listed in blue (note: putative polymorphisms affecting the two coding bases and five noncoding bases at each exon-intron junction were re-classified as splice site events). Large deletions affecting more then one exon and chromosomal re-arrangements are not listed on this map.

In the constitutional map, all individuals have a confirmed NF2 diagnosis unless indicated otherwise. Individuals listed as UVS have an NF2 diagnosis with a unilateral vestibular schwannoma plus other NF2 tumors.
Phenotypes of individuals meeting the expanded clinical criteria for NF2 are listed as mild, intermediate, or severe based on the authors' assessment or the criteria of Parry et al. and Evans et al. (for example, see Am J Med Genet 52: 450-461, Q J Med 84:603-618, or Friedman et al., Neurofibromatosis p. 308). Individuals reported as somatic mosaic (showing alteration in multiple unaffected tissues while low or absent in blood DNA) are giving the phenotype "KSM" for known somatic mosaic, typically without notation as to severity, and with additional phenotypic information if available. Alternative phenotypes such as single schwannoma and schwannomatosis are typically given without notation as to severity. Sporadic (non-inherited) multiple meningioma patients without BVS, although meeting the criteria for this map, are excluded because these tumors are thought to represent noncontiguous spread of a single tumor. These individuals will eventually be added to the somatic map.

In the somatic map, all individuals currently listed have a single tumor, which is assumed to be benign unless otherwise indicated. Phenotype abbreviations: MM = multiple meningiomas; VS = sporadic vestibular schwannoma. Tumor type is reported as given by the original author, and rough tumor location is given if provided by the author. Finally, the acronym "LOH" (for Loss of Heterozygosity) appears after the genetic sequence change if the mutated copy of the NF2 gene was the only allele present in the tumor, representing a loss of the functional NF2 copy in the process of tumor formation.

We have recently published a review article including a comprehensive meta-analysis of the data within these mutational maps.

Nunes, F., Ahronowitz, I., and MacCollin, M. Molecular Biology of Neurofibromatosis 2 and Related Conditions. Recent Res. Devel. Mol. Cell. Biol., 5(2004):171-196. Research Signpost. ISBN:81-7736-213-5.

Corrections, comments or additions to this map are welcome. Please address them to Mia MacCollin (note: for the email link to work, you must edit the email address to proper format).

Natural History Studies:

One of the most difficult aspects of having NF (or caring for a patient with NF) is not knowing what the future will bring.  Our lack of knowledge about the natural history of the tumors associated with NF1 and NF2 also makes the evaluation of potential therapies difficult.  In association with Children's Hospital of Boston and the House Ear Institute in Los Angles, the NF Clinic at MGH is participating in an international study to define the natural history of the tumors most commonly associated with NF.  Enrollment is limited to patients who are currently cared for at the clinic or one of the other participating centers.

  • Natural history study of vestibular tumors in NF2
  • Natural history study of plexiform neurofibroma in NF1

Patient-to-Patient Web Forum:

Mia MacCollin, M.D.
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Disclaimer About Medical Information: The information and reference materials contained herein is intended solely for the information of the reader. It should not be used for treatment purposes, but rather for discussion with the patient's own physician. All visitors to this and associated sites from the Neurosurgical Service at MGH agree to read and abide by the the complete terms of legal agreement found at the Neurosurgery "disclaimer & legal agreement." See also: the MGH Disclaimer, the MGH Privacy Policy, and the MGH Interactive Program Disclaimer - Copyright 2005.
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