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Page 344 Estévez-Arias et al. J Transl Genet Genom 2022;6:333-52 https://dx.doi.org/10.20517/jtgg.2022.04

[122]
studies . P participates in an adhesion-mediated signal transduction cascade, which even further supports
0
its essential role in myelination.
As mentioned above, from the clinical point of view, MPZ mutations have been linked to both infantile and
late onset of the disease, and some reports have proposed that early-onset neuropathy is related to
mutations that disrupt the tertiary structure of P and, thus, interfere with P -mediated adhesion and myelin
0
0
compaction, while late-onset neuropathy is caused by those that more subtly alter myelin structure,
probably disrupting Schwann cell-axonal interactions . This suggests that MPZ mutations that
[122]
predominantly affect myelination during development cause early-onset disease, while those that affect
axons cause late-onset disease.

Although the exact mechanism by which mutations in MPZ can lead to CMT disease is unknown, mutated
P has been linked to the unfolded protein response (UPR), which would cause defects in translation rate,
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folding, and/or membrane insertion. Furthermore, misfolded protein toxicity or reduced amounts of P
0
[121]
could be the etiology behind the phenotypic manifestations in patients carrying MPZ mutations . Given
that P is known to interact with lipid membrane surfaces [123,124] , mutations within P could also have direct
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0
[125]
effects on the formation of mature compact myelin at a molecular level .
Although a complete genotype/phenotype relationship has not been established, it is clear that two groups
of disease expressions can be delineated to classify the more than 200 different disease-causing mutations
that have been reported in MPZ until today.

PMP22
The PMP22 gene has been linked to CMT since the beginning of the genetic findings in this disease, and to
different phenotypic neuropathies since three mechanisms can lead to different disorders: (i) PMP22
overdose within CMT1A duplication causes the most common cause of the disease; (ii) point mutations of
PMP22 may be the underlying cause of more severe and early-onset forms, CMT types 1A or 1E; and (iii)
the monoallelic lack of PMP22 at 17p11.2 as a consequence of the 1.4 Mb deletion in the CMT1A locus
[126]
or point pathogenic variants can lead to hereditary neuropathy with liability to pressure palsies (HNPP).
[127]
As explained above, the overall prevalence of CMT is 1:2500, where 1:3800-12,500 corresponds to
CMT1A [128-130] .

The consequence of the 1.4 Mb CMT1A duplication or HNPP deletion is the expression of three copies or
one copy, respectively, of dose-sensitive PMP22. Thus, gene dosage has been the proposed pathological
mechanism, supported by the finding of increased protein and mRNA levels in CMT1A sural nerve
biopsies. Since PMP22 gene is under tight regulation, small changes can be expected to cause defects in
myelination and motor and sensory functions . Furthermore, regulation of PMP22 expression also occurs
[131]
during protein synthesis and translocation. From a histological point of view, PMP22 mutations are
characterized by onion bulb formations (CMT1A duplication) or tomaculae (HNPP deletion). A reduction
of myelinated fibers with signs of demyelination can be observed as a consequence of the functional impact
on PMP22 protein.

PMP22 encodes a 22 kDa glycoprotein produced primarily in Schwann cells and comprises 5% of proteins
of the PNS myelin . It is expressed in the compact portion of essentially all myelinated fibers in peripheral
[131]
[130]
nerves. It has been proposed as a key role player during Schwann cell growth and differentiation .
Nevertheless, the exact biological function is not clear yet. Proper folding and regulation of PMP22 are
essential for myelinating Schwann cells. Additionally, PMP22 promotes the organization of membrane