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Estévez-Arias et al. J Transl Genet Genom 2022;6:333-52 https://dx.doi.org/10.20517/jtgg.2022.04 Page 345

structure in compact myelin, plays a role in the maintenance of cholesterol homeostasis in Schwann cells,
[131]
and is involved in adhesion and cell proliferation . Finally, PMP22 point mutations are known to disrupt
PMP22 plasma membrane trafficking, resulting in misfolded proteins that are targeted by the ER, associated
with degradation for clearance. As this process is not 100% efficient, there is an accumulation of the
misfolded protein, which produces cellular stress .
[131]
It is important to remark that, apart from MPZ mutations, PMP22 mutations can be the cause of Dejerine-
Sottas syndrome, which occurs in the first two years of life .
[132]

Since this gene has been studied from the very beginning of genetic analysis in CMT, the knowledge around
it has been sufficient to design several drugs and/or therapeutic approaches, with the objective of regulating
its expression levels.

SH3TC2
[133]
SH3TC2 is associated with autosomal recessive demyelinating CMT type 4C (CMT4C) . This type of
CMT shows an early onset, characterized by unsteadiness, distal weakness, occasional cranial nerve
involvement (hearing loss, pupillary abnormalities, and/or tongue atrophy), and foot and spinal
deformities [134,135] . Traditionally, these features have been explained by the important sensory loss inherent to
this type of CMT. However, the important vestibular impairment that was confirmed in previous depth
[134]
characterizations of CMT4C patients should also be mentioned . SH3TC2-related CMT cases are not
distributed randomly, and several studies have shown substantial differences between countries [132,133,136] .
Specifically, SH3TC2-causative variants have been proven to have a high prevalence in Spanish Gypsy
cohorts of patients .
[137]

SH3TC2 encodes an effector molecule of Rab11, which is found in myelinating Schwann cells and expressed
late during myelination, thus is essential in the maintenance of the structural integrity of peripheral nerve
myelin sheaths . To date, more than 70 mutations in this gene have been reported (dispersed throughout
[133]
the protein) and proven to influence the peripheral nerve pathophysiology. Specifically, SH3TC2
participates in the endocytic pathway of cell traffic, and, therefore, it can be found in clathrin-coated vesicles
(including the trans-Golgi-network, early and late endosomes, and specific domains of the plasma
membrane). This localization is dependent on protein myristoylation and interactions, for which both its
[138]
SH3 and TRP domains are essential . Furthermore, evidence has been presented on its role in the
Nrg1/ErbB signaling pathway during early postnatal development of the PNS, suggesting that CMT4C
patient’s hypomyelination may be explained, at least in part, as a consequence of the dysregulation of this
[139]
signaling pathway . As a consequence of these molecular abnormalities, in biopsies of SH3TC2-patients,
concentric Schwann cell proliferation with multiple small onion bulbs can be observed, with the
involvement of unmyelinated fibers.

SORD
Sorbitol dehydrogenase gene (SORD) has recently been identified as a causative gene of recessive forms of
hereditary neuropathy, both CMT type 2 and distal hereditary motor neuropathy (dHMN) . This gene
[140]
encodes a protein that acts as a key enzyme in the polyol pathway, which is an alternate route for sugar
metabolism . SORD catalyzes the interconversion between glucose and fructose via sorbitol, together with
[141]
aldose reductase. Due to that, this protein is believed to be involved in the development of diabetic
neuropathy .
[141]