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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 341

women are affected, males have moderate to severe symptoms, while heterozygous females may remain
asymptomatic or may have mild CMTX1, being the skewed X-inactivation the likely explanation for the
reduced severity. It should be noted that in those cases where women are severely affected, the most
[76]
promising explanation is the non-random X-inactivation in each myelinating cell .

It should be noted that the nerve conduction velocities in patients with CMT-GJB1 are in the intermediate
range: faster than in patients with the demyelinating forms (CMT1) and slower than axonal/neuronal forms
(CMT2); however, in female cases, NCVs are often preserved. Moreover, median nerve conductions appear
to be generally more severely affected than those of the ulnar nerve [77,78] . Finally, in nerve biopsies, the most
prominent finding is the increasing number of regenerated axon clusters, together with an age-related loss
[79]
of myelinated fibers .

The GJB1 gene encodes a member of a large family of connexins. Specifically, GJB1 encodes connexin 32, a
protein that is remarkedly present in Schwann cells and oligodendrocytes, which are the myelinating glia of
[74]
the peripheral and central nervous systems, respectively . This explains why patients with CMT1X can
have both central and PNS manifestations.

Six connexins molecules form a hemichannel, arranged around a central pore. Two of these hemichannels
form a gap junction channel, allowing the formation of a link between two cells. Tens to thousands of these
connexin channels are localized along the cell membrane, creating what is known as gap junction
plaques . Thanks to these channels, ions, signaling molecules, and/or small metabolites can diffuse
[72]
[74]
between cells, helping them to couple in electrical and chemical ways, between other functions . In
Schwann cells, Cx32 is localized to the non-compact myelin of the paranodes and Schmidt-Lantermann
incisures, where it forms gap junctions between adjacent loops of non-compact myelin, predicted to provide
a radial diffusion pathway [80-85] . This means that, in Schwann cells, Cx32 forms a reflexive pathway between
the abaxonally located nucleus of the Schwann cells and the adaxonal region .
[80]
Since the first report that mutations in GJB1 cause CMT1X, more than 400 mutations were predicted to
impact protein function. Many of them could be predicted to cause loss-of-function effect, although the
mechanisms could differ: nonsense or frameshift mutations that affect the N-terminal part, mutations that
affect the promoter region [86,87] , or large deletions involving the entire coding region of the gene would not
be expected to produce functional channels .
[88]

The biological mechanisms by which the different mutations can lead to this total or partial loss of function
are diverse: reduction of the minimal luminal dimension (that would affect the diffusion of specific small
[89]
molecules) , increasing sensitivity to acidification-induced closure, or stabilization of the closed state of the
channel are some examples of the biophysical alterations that have been explored. Moreover, it has been
[90]
analyzed how the junctional coupling can be affected by mutations in this gene, due to reduced steady-state
levels of the protein .
[90]

Although the most common pathogenic mechanism of GJB1 mutations is this loss-of-function, some
studies have reported gain-of-function mechanisms of some Cx32 mutants . Overall, clinical studies
[91]
suggest that the peripheral manifestations of CMT1X are likely to be due to loss-of-function, while in the
central nervous system gain-of-function may contribute .
[80]