E. Fabbretti et al., APOPTOTIC PHENOTYPE INDUCED BY OVEREXPRESSION OF WILD-TYPE GAS3 PMP22- ITS RELATION TO THE DEMYELINATING PERIPHERAL NEUROPATHY CMT1A/, Genes & development, 9(15), 1995, pp. 1846-1856
Although the Gas3/PMP22 protein is expressed at highest levels in diff
erentiated Schwann cells, its presence, albeit at lower levels, in non
-neuronal tissues and in NIH-3T3 growth-arrested fibroblasts argues fo
r a more general function of this protein that is uncoupled to myelin
structure. We show that gas3/PMP22 overexpression in NIH-3T3 growing c
ells leads to an apoptotic-like phenotype, which is suppressed by anti
oxidants and characterized by typical membrane blebbing, rounding up,
and chromatin condensation, but with no evidence of DNA fragmentation.
REF-52 fibroblasts seem to be completely refractive to gas3/PMP22 ove
rexpression. Recently, several point mutations of the human gas3/PMP22
gene have been associated with Charcot-Marie-Tooth type 1A (CMT1A), a
common hereditary demyelinating neuropathy. When gas3/PMP22 point mut
ations (L16P, S79C, T118M, and G150D) are similarly overexpressed in N
IH-3T3 cells, the induced apoptotic-like phenotype as compared to the
wild-type is significantly reduced. Both of the dominant mutations (L1
6P, S79C) for CMT1A behave as dominant negatives with respect to the w
ild type, whereas T118M, the only recessive mutant described, behaves
as recessive under the same coexpression experiments. These data sugge
st a role for altered Schwann cell apoptosis in the pathogenesis of CM
T1A.