Neurofibromatosis 1 Somatic Mutation Triggering Cellular Apoptosis to Prevent Neurofibromatosis 1 Progression

Abstract

Persons with ordinary, prototypical Neurofibromatosis 1 (NF1)
are born with a germinal/zygotic mutation at the NF1 locus
on the long arm of chromosome 17 (17q) present in all of their
cells. An NF1 germinal mutation is the “first hit,” accounting for
haploinsufficiency at the NF1 locus. The NF1 somatic mutation
is the “second hit,” accounting for diploinsufficiency (deranged or
lost function of both alleles) at the NF1 locus. The NF1 somatic
mutation occurs in a variety of somatic (i.e., non-germinal) cells,
including, and especially the schwann cells (SC). I suggest that
NF1 haploinsufficiency provides the conditions for the SC (and
other cells) to develop NF1 diploinsufficiency rather than NF1
diploinsufficiency developing independently of the conditions in
which it originates. In either case, imagine a viral analogue with an
apoptosis trigger held in abeyance unless an NF1 somatic mutation
occurs in the presence of an NF1 germinal mutation or whole
gene deletion. That is, instead of altering the feature, for example,
decreasing neurofibroma size and symptoms with MEK inhibitors,
I herein suggest an approach to preventing certain NF1 features,
keying off the fact that almost NF1 features involve somatic
mutation of the cell’s NF1 wild type (WT) allele.