Recent progress in human genetics and neurobiology has led to the
identification of various mutations in
particular myelin genes as the cause for many of the known inherited
demyelinating peripheral
neuropathies. Mutations in 3 distinct myelin genes, PMP22, P0,
and connexin 32 cause the 3 major
demyelinating subtypes of Charcot-Marie-Tooth (CMT) disease, CMT1A, CMT1B
and CMTX, respectively.
In addition, a reduction in the gene dosage of PMP22 causes hereditary
neuropathy with liability to pressure
palsies (HNPP), while particular point mutations in PMP22 and P0
cause the severe Dejerine-Sottas (DS)
neuropathy. A series of spontaneous and genetically engineered rodent mutants
for genes for the above-mentioned myelin constituents are now available
and their suitability to serve as models for these still
untreatable diseases is an issue of particular interest. The spontaneous
mutants Trembler-J and Trembler,
with point mutations in PMP22, reflect some of the pathological alterations
seen in CMT1A and DS
patients, respectively. Furthermore, engineered mutants that either over
or
underexpress particular myelin
genes are suitable models for patients who are similarly compromised in
the
gene dosage of the
corresponding genes. In addition, engineered mutants heterozygously or
homozygously deficient in the
myelin component P0 show the pathology of distinct CMT1B and
DS
patients, respectively, while Cx32
deficient mice develop pathological abnormalities similar to those of CMTX
patients. Mutants that mimic
human peripheral neuropathies might allow the development of strategies
to
alleviate the symptoms of the
diseases, and help to define environmental risk factors for aggravation
of the
disease. In addition, such
mutants might be instrumental in the development of strategies to cure
the
diseases by gene therapy.