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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 343

[67]
that MFN2, similar to GDAP1, is a tethering protein between mitochondria and lysosomes . Studies to
shed light on the pathophysiology of MFN2 mutations have been performed in nervous tissues and
fibroblasts from patients, as well as in mice and motor neurons derived from induced pluripotent cells
(iPSCs) obtained from fibroblasts. However, the results are quite controversial since some of the changes
can only be observed in some studies but do not extend to all of them: for instance, there is still little
agreement regarding whether there are alterations in MFN2 protein levels, in the respiratory chain capacity
and oxidative phosphorylation, in mitochondrial membrane potential, or mtDNA content [101,112-114] .

Most missense variants reside within MFN2 dynamin-GTPase domain [115,116] , and there is recent evidence
that a dominant-negative or gain-of-function effect may be responsible for the pathogenicity. Other
evidence shows that some variants are responsible for mitochondrial hypofusion, while others can cause
[117]
mitochondrial hyperfusion . Moreover, as explained above, autosomal recessive and semidominant forms
[118]
of CMT2A2 have been reported. This further illustrates the allelic heterogeneity of this condition .
Even with differences between studies, it is clear that there are mitochondrial abnormalities in MFN2
patients. Mitofusin-2 represents a key player in several mitochondrial activities: fusion, trafficking, turnover,
and contacts with other organelles and the consequences of mutations in the MFN2 gene disbalance the
appropriate mitochondrial shape, function, and distribution within the cell . Alterations in mitochondrial
[119]
transport and distribution likely cause a bioenergetics impairment, especially in highly metabolic cells,
which is the case for neurons. These disrupted and affected processes lead to a loss of myelinated fibers and
mitochondrial abnormalities, visible in nerve biopsies.

MPZ
Mutations in MPZ commonly result in autosomal dominant neuropathy and are estimated to account for
5% of cases of CMT . In this gene, the phenotypical heterogeneity that can be found is remarkable, in
[26]
regards to both the severity of the symptoms and the neurophysiological parameters.

Myelin protein zero (P ), which is part of the immunoglobulin gene superfamily, is a major peripheral
0
protein that acts as a homophilic adhesion molecule and is crucial for compact myelin formation and
maintenance in the PNS . It is the most abundant myelin protein produced in myelinating Schwann cells.
[120]
It has been related to CMT and can cause the three different types of the disease: demyelinating, axonal, and
intermediate forms. Consequently, individuals carrying MPZ mutations have a variety of clinical
phenotypes, from severe disease with early onset of weakness and sensory loss in the neonatal period
associated with very low NCVs (Dejerine-Sottas syndrome) to a much milder disease with onset of
symptoms in the fourth decade of life with minimal slowed NCVs (CMT2). However, variability also exists,
since late-onset patients can be quite severe, too (even confined to a wheelchair), and onset can last until the
eighth decade of life. In nerves, signs of demyelination/remyelination with myelin outfoldings and onion
bulb formations are the most characteristics features.

The structure of P is divided into three different domains: extracellular, transmembrane, and cytoplasmatic
0
domains. Interestingly, most of the described mutations can be found in the extracellular part, which is
essential for establishing interactions. P forms homotetramers within the cell membrane: each
0
homotetramer interacts in trans with a similar homotetramer on the opposing membrane surface.
Furthermore, P tethers appose lipid bilayers together through its extracellular immunoglobulin-like
0
domain . This is the reason it was proposed as having a key role in myelination, as P holds together
[121]
0
adjacent wraps of myelin membrane through these homotypic interactions. Not only the extracellular part is
essential to establish these interactions, but also the cytoplasmatic domain, as has been shown in different