Human Molecular Genetics, Vol 6, 1707-1712, Copyright © 1997 by Oxford University Press
GR Skuse and AJ Cappione
Neurofibromatosis type 1 (NF1) is a common genetic disorder which
predisposes affected individuals to a variety of clinical features
including tumors of the central and peripheral nervous systems. The product
of the NF1 gene, neurofibromin, is a tumor suppressor which most likely
acts through the interaction of its GTPase activating protein (GAP) related
domain (GRD) with RAS to regulate cellular growth. Two intriguing features
of NF1 are the wide range of potentially affected tissues and the great
variation in expressivity of disease traits across those affected. To date,
the underlying source of this variation remains somewhat unclear, but
evidence suggests that aberrations in normal NF1 RNA processing may be
involved. This evidence includes: (i) differences in the relative ratios of
the type I and type II splice variants in NF1 tumors compared with nontumor
tissues; (ii) unequal expression of mutant and normal NF1 alleles in
cultured cells derived from NF1 patients; (iii) the existence of NF1 tumors
which display NF1 mRNA editing levels that are greater than that seen in
non- NF1 tumors; and (iv) tissue-specific and developmental stage-specific
expression of particular alternative NF1 transcripts. These findings
suggest that the classical 2-hit model for tumor suppressor inactivation
used to explain NF1 tumorigenesis can be expanded to include the
post-transcriptional mechanisms which regulate NF1 gene expression.
Aberrations in these mechanisms may lead to the pathogenesis of NF1 and may
play a role in the observed clinical variability.
REVIEWS
RNA processing and clinical variability in neurofibromatosis type I (NF1)
Department of Medicine, University of Rochester School of Medicine and Dentistry, New York 14642, USA. gary_skuse@medicine.rochester.edu
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