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
also NF2 Map References):
Constitutional Map 1-9.jpg | 2006
Constitutional Map 1-9.tif ]
Constitutional Map 10-17.jpg |
Map 10-17.tif ]
Somatic Map 10-17.jpg | 2006
Somatic Map10-17.tif ]
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as well as verified unpublished mutations found by our group.
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.
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.
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
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: